Sequential combination of mitomycin C plus bacillus Calmette-Guérin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial.

BACKGROUND: Intravesical bacillus Calmette-Guérin (BCG) is an effective therapy in non-muscle-invasive bladder cancer (NMIBC), but it has limitations in terms of recurrence and toxicity. OBJECTIVE: To determine whether the sequential combination of mitomycin C (MMC) and BCG is superior to BCG alone in increasing a disease-free interval (DFI). DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective randomized trial including 407 patients with intermediate- to high-risk NMIBC and allocated 211 to the MMC and BCG arm and 196 to the BCG-alone arm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The trial was designed to provide concurrently a power of 80% for the detection of a relative risk reduction of 35% (hazard ratio [HR]: 0.65) of disease relapse with a type I error of 0.05. Times to events were estimated using cumulative incidence functions and compared using the Cox regression model. We used the Kaplan-Meier technique to estimate survival curves. RESULTS AND LIMITATIONS: In the intention-to-treat analysis at 5 yr, DFI was significantly improved by the sequential scheme (HR: 0.57; 95% confidence interval [CI], 0.39-0.83; p=0.003), reducing the disease relapse rate from 33.9% to 20.6%. Higher toxicity was observed with the combination, even reducing the MMC dose, especially in G3 local toxicity compared with BCG with a difference of 17.4% (95% CI, 7.6-27.2; p<0.001). In recurrent T1 tumors, the potential benefit of the sequential scheme was more evident than in the remaining subgroup (18.8% vs 12.8%), with a number needed to treat of five versus eight to avoid an event and with similar toxicity. CONCLUSIONS: Although the sequential scheme is more effective than BCG alone in reducing disease relapse, due to higher toxicity it could be offered only to patients with a high likelihood of recurrence, such as those with recurrent T1 tumors. PATIENT SUMMARY: We analyzed the outcomes of a randomized trial demonstrating that in intermediate- to high-risk non-muscle-invasive bladder cancer, mitomycin C and bacillus Calmette-Guérin (BCG) reduced disease relapse compared with BCG alone but was more toxic. Consequently, it could be offered only to patients with recurrent T1 tumors. TRIAL REGISTRATION: CUETO 93009.

Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy.

OBJECTIVE: To report long-term outcomes of selective organ preservation for muscle-invasive bladder cancer (MIBC) using 2 bladder-sparing trimodality approaches. MATERIALS AND METHODS: From 1990 to 2010, 80 patients with T2-T4 bladder cancer were prospectively enrolled in 2 successive bladder-sparing protocols. Forty-one patients were treated with neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy followed by radiotherapy (60 Gy) in complete responders (protocol 1 [P1]) and 39 patients were treated with weekly cisplatin concurrent with radiotherapy (64.8 Gy) (protocol 2 [P2]). RESULTS: The median follow-up was 72 months (range, 9-204 months). Five and 10-year cumulative overall survival for all series were 73% and 60% and the corresponding numbers for cancer-specific survival were 82% and 80%, respectively. Of all surviving patients, 83% maintained their own bladder. Although there were no significant differences in overall survival (P = .820), cancer-specific survival (P = .688) and distant metastasis (P = .417) between protocols, complete response rates (P = .003), and disease-free survival (P = .031) were significantly higher in P2 treatment. CONCLUSION: Trimodality therapy with bladder preservation represents a real alternative to radical cystectomy (RC) in selected patients. Overall survival and cancer-specific survival rates are encouraging with more than 80% of survivors retaining functional bladders.

The EORTC tables overestimate the risk of recurrence and progression in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: external validation of the EORTC risk tables.

BACKGROUND: European Organization for Research and Treatment of Cancer (EORTC) risk tables only included 171 patients treated with bacillus Calmette-Guérin (BCG) for non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To evaluate the external validity of the EORTC tables in patients with NMIBC treated with BCG over 5-6 mo. DESIGN, SETTING, AND PARTICIPANTS: Data on 1062 patients treated with BCG were analyzed. MEASUREMENTS: Discrimination was assessed using the concordance index (c-index) and the prognostic separation index (PSEP). For calibration, probabilities of recurrence and progression obtained with the EORTC risk tables in our series were compared with those reported by the EORTC. RESULTS AND LIMITATIONS: With respect to the discriminative ability of the EORTC model, c-index was similar to those reported in the EORTC series for recurrence. However, c-indices for progression in our series were lower than c-indices reported by Sylvester et al. [1]. Although PSEP in our series was lower than in the EORTC series for recurrence at 1 yr, similar results were found at 5 yr. Regarding progression, PSEP in our series was lower than in the EORTC series. Whilst a successful stratification of recurrence and progression probability at 1 and 5 yr was achieved using the EORTC tables in our series, model calibration showed lower risks of recurrence than those reported by Sylvester et al. [1] in all groups. For progression, lower risks were found in higher-risk groups. There are some limitations in the present study. A different distribution of patients was found, with higher proportions of primary grade 3 T1 tumors and tumors in situ than in the EORTC series. An additional limitation is that prior recurrence of the EORTC table was not included in our parameters. Consequently, two separate analyses were performed for recurrence. CONCLUSIONS: The EORTC model successfully stratified recurrence and progression risks in our cohort. However, the discriminative ability of the EORTC tables decreased in our patients for progression. Moreover, these tables overestimated risks of recurrence and progression after BCG therapy.

Long-term results after high-dose radiotherapy and adjuvant hormones in prostate cancer: how curable is high-risk disease?

PURPOSE: To analyze long-term outcome and prognostic factors for high-risk prostate cancer defined by National Comprehensive Cancer Network criteria treated with high-dose radiotherapy and androgen deprivation in a single institution. METHODS AND MATERIALS: A total of 306 patients treated between 1995 and 2007 in a radiation dose-escalation program fulfilled the National Comprehensive Cancer Network high-risk criteria. Median International Commission on Radiation Units and Measurements radiation dose was 78 Gy (range, 66.0-84.1 Gy). Long-term androgen deprivation (LTAD) was administered in 231 patients, short-term androgen deprivation (STAD) in 59 patients, and no hormones in 16 patients. The Phoenix (nadir plus 2 ng/mL) consensus definition was used for biochemical control. Multivariate analysis was performed to determine the independent prognostic impact of clinical and treatment factors. Median follow-up time was 64 months (range, 24-171 months). RESULTS: The actuarial overall survival at 5 and 10 years was 95.7% and 89.8%, respectively, and the corresponding biochemical disease-free survival (bDFS) was 89.5% and 67.2%, respectively. Fourteen patients (4.6%) developed distant metastasis. Multivariate analysis showed that Gleason score>7 (p=0.001), pretreatment prostate-specific antigen (PSA) level>20 ng/mL (p=0.037), higher radiation dose (p=0.005), and the use of adjuvant LTAD vs. STAD (p=0.011) were independent prognostic factors affecting bDFS in high-risk disease. The 5-year bDFS for patients treated with LTAD plus radiotherapy dose>78 Gy was 97%. CONCLUSIONS: For high-risk patients the present series showed that the use of LTAD in conjunction with higher doses (>78 Gy) of radiotherapy was associated with improved biochemical tumor control. We observed that the presence of Gleason sum>7 and pretreatment PSA level>20 ng/mL in the same patient represents a 6.8 times higher risk of PSA failure. These men could be considered for clinical trials with addition of novel agents.

Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model.

PURPOSE: Bacillus Calmette-Guerin is the most effective therapy for nonmuscle invasive bladder cancer. Recently to calculate the risks of recurrence and progression based on data from 7 European Organisation for Research and Treatment of Cancer trials a scoring system was reported. However, in that series only 171 patients were treated with bacillus Calmette-Guerin. We developed a risk stratification model to provide accurate estimates of recurrence and progression probability after bacillus Calmette-Guerin. MATERIALS AND METHODS: Data were analyzed on 1,062 patients treated with bacillus Calmette-Guerin and included in 4 Spanish Urological Club for Oncological Treatment trials. Stepwise multivariate Cox models were used to determine the effect of prognostic factors. In each patient the weight of all factors was summed to a total score. Patients were then divided into groups, and cumulative recurrence and progression rates were calculated. RESULTS: A scoring system was calculated with a score of 0 to 16 for recurrence and 0 to 14 for progression. Patients were categorized into 4 groups by score, and recurrence and progression probabilities were calculated in each group. For recurrence the variables were gender, age, grade, tumor status, multiplicity and associated Tis. For progression the variables were age, grade, tumor status, T category, multiplicity and associated Tis. For recurrence calculated risks using Spanish Urological Club for Oncological Treatment tables were lower than those obtained with Sylvester tables. For progression probabilities were lower in our model only in patients with high risk tumors. CONCLUSIONS: We propose a scoring model to stratify the risk of recurrence and progression in patients treated with bacillus Calmette-Guerin.

Is hormone therapy a protective factor for late hematuria after high-dose radiotherapy in prostate cancer?

OBJECTIVES: To identify potential clinical and dosimetric factors predictive of a higher risk of grade 2 or higher late hematuria in patients with prostate cancer treated with high-dose radiotherapy. METHODS: For this purpose, we have analyzed 229 T1c-T3b prostate cancer patients treated with 3-dimensional conformal radiotherapy (3DCRT) in a prospective dose escalation study and with a minimum follow-up of 1 year. The mean radiation dose was 79 Gy (range 72.1 to 84.14 Gy) and the mean follow-up was 47 months (range 14 to 95). One hundred eighteen patients also received androgen deprivation (AD) for high-risk disease. Univariate and multivariate analysis (MVA) were performed to identify variables significantly associated with late hematuria. RESULTS: Of the 31 (14%) patients with grade 2 or higher genitourinary toxicity, hematuria was the main symptom in 24 (10.5%) with only 1 patient (0.5%) experiencing grade 3 hematuria. On statistical analysis, all the dosimetric parameters failed to show a significant correlation with grade 2 or higher hematuria. On MVA, prior transurethral resection of the prostate (TURP) was significantly associated with a higher risk of late hematuria (relative risk [RR] = 2.8; P = 0.026), whereas long-term AD was correlated with a significantly decreased risk (RR = 0.21; P = 0.019). CONCLUSIONS: TURP was a relevant factor increasing 3 times the risk of late hematuria in prostate cancer patients treated with 3DCRT. Conversely, long-term AD resulted in a protective factor decreasing 5 times the risk of late hematuria. To our knowledge, this is the first study reporting a protecting effect of long-term hormones in late toxicity after radiotherapy.

Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials.

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.

Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial.

PURPOSE: We determined if a third of the dose of intravesical bacillus Calmette-Guerin (BCG) has the same efficacy than a standard dose for decreasing the risk of recurrence and progression after transurethral resection in patients with superficial high risk (stages T1G3 and carcinoma in situ) bladder cancer. Also, we evaluated toxic side effects. MATERIAL AND METHODS: A total of 155 patients with a mean age +/- SD of 67 +/- 10.1 years with superficial bladder cancer, including stages T1G3 in 90, a Tis primary tumor in 23 and associated Tis disease in 42, were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG, Connaught strain (weekly x 6 and fortnightly x 6 thereafter) with the standard dose of 81 mg or with the decreased dose of 27 mg. RESULTS: Median followup was 61 months (range 3 to 102). Disease recurred in 32 patients (39%) treated with the standard dose and in 33 (45%) treated with the decreased dose. Median time to recurrence was not attained in the standard dose arm and it was 63 months in the decreased dose arm. Kaplan-Meier estimates for time to recurrence did not reveal differences between the 2 doses (p = 0.405). Tumor progressed in 20 patients (24.7%) with the standard dose and in 19 (26%) with the decreased dose. Four patients (6.1%) with Tis had local extension into the prostatic urethra and ducts, including 3 (8.3%) treated with the standard dose and 1 (3.4%) treated with the decreased dose. Median time to progression was not attained in either arm. Kaplan-Meier estimates for time to progression did not differ significantly (p = 0.7997). Deferred cystectomy for progression was performed in 7 patients (8.4%) treated with the standard dose and in 7 (9.5%) of those treated with the decreased dose. Subgroup analysis by patient age, tumor status, number, size and T stage (T1G3 vs Tis) did not differ significantly. The groups did not differ in disease specific mortality, which was 12.2% in the standard dose arm and 16.4% in the decreased dose arm. Mean disease specific survival +/- SE was 86.96 +/- 4.14 and 83.73 +/- 4.73 months, respectively. CONCLUSIONS: Our results suggest that a 3-fold decreased dose of intravesical BCG is as effective as the standard dose against progression in patients with high risk stages T1G3 and Tis superficial bladder carcinoma but with significantly less toxicity.