Juan Casanova

EFFECTIVENESS OF A SINGLE IMMEDIATE MITOMYCIN C INSTILLATION IN PATIENTS WITH LOW RISK SUPERFICIAL BLADDER CANCER: SHORT AND LONG-TERM FOLLOWUP

PURPOSE We analyze the impact of a single mitomycin C instillation in patients with low risk superficial bladder cancer with short and long-term followup. MATERIALS AND METHODS A total of 131 patients with low risk superficial bladder cancer were included in a prospective randomized controlled trial. All patients had a 3 cm or less single, papillary, primary or recurrent tumor and were disease-free for more than 1 year. Patients with muscular invasion, G3 tumor or bladder carcinoma in situ on pathological examination were excluded from study. The tumor was completely resected before patients were randomized into 2 arms of no further treatment (control group) and a single immediate instillation of 30 mg mitomycin C (mitomycin C group). Recurrences were considered early within the first 2 years of followup. RESULTS At 24-month followup the recurrence-free interval was significantly increased, and recurrence, and recurrence and tumor per year rates were decreased in the mitomycin C compared to the control group. However, at long-term followup these differences were not statistically significant and the recurrence-free interval curves were parallel. A shorter hospital stay and catheterization period were noted in the mitomycin C group compared to the control group, which were not significant. Early recurrences were concentrated in the first year in the control but not in the mitomycin C group. A significant relationship between early and late recurrences was found in the mitomycin C but not in the control group. CONCLUSIONS Our analysis confirms the positive effect of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer. This benefit is limited to early recurrence and is not maintained with long-term followup. Thus, this approach is an alternative to observation or endovesical chemotherapy. Our study also suggests that cell implantation as a mechanism of early recurrence can be controlled with a single mitomycin C instillation.

PROSPECTIVE VALIDATION OF THE ASSOCIATION OF LOCAL TUMOR STAGE AND GRADE AS A PREDICTIVE FACTOR FOR OCCULT LYMPH NODE MICROMETASTASIS IN PATIENTS WITH PENILE CARCINOMA AND CLINICALLY NEGATIVE INGUINAL LYMPH NODES

PURPOSE We prospectively validated the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative lymph nodes. MATERIALS AND METHODS In a retrospective study of 66 patients we demonstrated the predictive value of the association of local tumor stage and grade for occult micrometastasis, identifying 3 risk groups. A therapy strategy was designed according to these risk groups. A total of 37 consecutive patients were included in a prospective study in which the same criteria for risk group allocation and the same therapeutic recommendations were used as in the retrospective study. RESULTS In the prospective study we noted positive lymph nodes in 11% of stage T1, 63% of stages T2-3, 15% of grade 1, 67% of grade 2 and 75% of grade 3 cases. The incidence of positive nodes was 0% in the low, 83.3% in the high and 33.3% in the intermediate risk group. These rates were similar to those in the retrospective study with no significant difference. CONCLUSIONS The predictive value of the association of local tumor stage and grade for occult lymph node micrometastasis was validated in a prospective study. This factor allows the differentiation of 3 risk groups of patients with high reliability in the low and high risk groups. However, other prognostic factors are needed in the intermediate risk group to improve the prediction of lymph node involvement.

THE 3-MONTH CLINICAL RESPONSE TO INTRAVESICAL THERAPY AS A PREDICTIVE FACTOR FOR PROGRESSION IN PATIENTS WITH HIGH RISK SUPERFICIAL BLADDER CANCER

PURPOSE We analyzed the 3-month clinical response to intravesical therapy as a factor predictive of progression in patients with high risk superficial bladder cancer. MATERIAL AND METHODS We evaluated 191 patients with high risk superficial bladder cancer, 111 with secondary or associated bladder carcinoma in situ and 80 with stage T1 grade 3 disease who were treated with intravesical therapy. We considered only clinically complete and no responses at the 3-month endoscopic study. To determine the predictive value of the 3-month clinical response we differentiated progression into superficial and invasive types. RESULTS At a median followup of 73 months 91 patients (47.6%) had progression, which was superficial in 48 (25. 1%) and invasive in 43 (22.5%). Invasive progression was associated with significantly higher cause specific mortality than superficial progression (p = 0). In the latter cases cause specific mortality was higher than in those without progression (p = 0.001). Although cystectomy significantly decreased the cause specific mortality rate in patients with invasive progression (p = 0.0001), this rate was high at 46.3%. Univariate and multivariate analyses revealed that the 3-month clinical response was a significant predictive factor for progression. Moreover, stratifying this variable showed that this response was the only independent factor predictive of invasive progression in cases of no response with stage T1 grade 3 tumor, bladder carcinoma in situ, or prostate mucosa or duct involvement (p = 0). In our series 41 patients (21.5%) did not respond after intravesical therapy at the 3-month evaluation, including 29 with stage T1 grade 3 disease, bladder carcinoma in situ, or prostate mucosa or duct involvement. Progression in 24 of these 29 patients (82.3%) was classified as invasive in 21 (73.6%). CONCLUSIONS Invasive progression threatens the cause specific survival of patients with high risk superficial bladder cancer even when cystectomy is performed. The 3-month clinical response was an excellent predictive factor for invasive progression. Early cystectomy should be considered when stage T1 grade 3 tumor, bladder carcinoma in situ, or prostate mucosa or duct involvement is present at the 3-month clinical evaluation.

FEASIBILITY OF TRANSURETHRAL RESECTION FOR MUSCLE INFILTRATING CARCINOMA OF THE BLADDER: LONG-TERM FOLLOWUP OF A PROSPECTIVE STUDY

PURPOSE We analyzed the long-term results of radical transurethral resection for the treatment of a large series of patients with muscle infiltrating bladder cancer entered into a prospective study to determine progression predictive factors. MATERIALS AND METHODS The study included 133 patients with invasive bladder cancer treated by radical transurethral resection who had negative biopsies of the muscle layer of the tumor bed. Followup was more than 5 years for all subjects and more than 10 years in 59 (44.4%). A comparative nonrandomized study was performed of a control group of 76 patients with invasive pathological stage pT2-3a, N0-3 bladder cancer treated by cystectomy. In those patients treated by radical transurethral resection univariate and multivariate analyses were performed to establish clinical progression predictive factors. RESULTS At 5 and 10 years of followup cause specific survival rates were 80.5 and 74.5%, and bladder preservation rates were 82.7 and 79.6%, respectively. No significant difference was noted in terms of cause specific survival, with respect to the control group. The initial presence of associated bladder carcinoma in situ was the only independent progression predictive factor. CONCLUSIONS For patients with invasive bladder cancer radical transurethral resection is justified when the tumor is clinically limited to the muscular layer and when all biopsies of the periphery and depth of the tumor bed show muscular tissue negative for tumor cells. Patients with initial associated bladder carcinoma in situ should not be excluded from this treatment but endovesical bacillus Calmette-Guerin immunotherapy should be administered and a closer followup is recommended.

Conservative elective treatment of upper urinary tract tumors: a multivariate analysis of prognostic factors for recurrence and progression.

PURPOSE We evaluate the safety and efficacy of conservative elective treatment of upper urinary tract tumors, and determine predictive factors for recurrence and progression to optimize indications of this type of treatment. MATERIALS AND METHODS Since 1984 we have performed a prospective study of conservative treatment of single, low grade and stage, less than 3 cm. upper tract tumors. The study includes 54 patients with a normal contralateral kidney who had been followed for more than 36 months. Open conservative surgery was performed in 31 cases and endourological surgery in 23. Minimum followup was 36 months, maximum 210 and mean 84.8. Univariate and multivariate analyses of recurrence and progression were performed in relation to age, sex, association with a bladder tumor, bladder tumor stage and grade, sequence of bladder tumor in relation to upper urinary tract tumor, number of previous bladder tumor recurrences, association with bladder carcinoma in situ, upper urinary tract tumor grade, stage, location, size and therapy, and upper urinary tract cytology. RESULTS Of the 54 patients 19 (35%) had recurrence, which was bilateral recurrence in 4, and progression occurred in 9 (16%). At the end of analysis 44 (62.9%) patients were disease-free and alive at a mean time of 92.88 months, 13 (24%) died disease-free at a mean of 72.7 months and 7 (12.9%) died of disease at a mean of 97.85 months. Cause specific mortality occurred in 7 (12.9% cases). Among the 54 initially conservatively treated units 42 (77.7%) kidneys were ultimately preserved. On univariate and multivariate analysis tumor location in the renal pelvis and association with a previous multi-recurrent bladder tumor were variables significantly related to recurrence and progression, as well as bilateral recurrence. CONCLUSIONS Conservative treatment is an optional approach for select upper urinary tract tumors. The strongest risk factors for recurrence and progression were association with a previous multi-recurrent bladder tumor and tumor location in the renal pelvis but these conditions were also the strongest risk factors for bilateral recurrence. Conservative treatment can also be recommended in these cases but only with compliant patients and close followup.

Identification of miR-187 and miR-182 as Biomarkers of Early Diagnosis and Prognosis in Patients with Prostate Cancer Treated with Radical Prostatectomy

PURPOSE miRNAs are noncoding RNAs that negatively regulate target mRNA gene expression. Aberrant miRNA expression is associated with prostate cancer pathogenesis. We identified miRNAs as potential biomarkers for prostate cancer diagnosis and prognosis. MATERIALS AND METHODS Total RNA was obtained from 10 normal prostate and 50 prostate cancer samples, and analyzed using the GeneChip® miRNA 2.0 Array. At a median followup of 92 months (range 2 to 189) an independent cohort of 273 paraffin embedded prostate cancer samples was used for validation by quantitative reverse transcriptase-polymerase chain reaction. Another 92 urine samples from patients undergoing prostate biopsy were evaluated for these miRNAs. RESULTS miR-182 and 187, the miRNAs most differentially expressed between normal and tumor tissue, were selected for further validation. miR-187 inversely correlated with cT (p = 0.125) and pT (p = 0.0002) stages, Gleason score (p = 0.003) and TMPRSS2-ERG status (p = 0.003). The log rank test showed associations of miR-182 with biochemical (p = 0.026) and clinical (p = 0.043) progression-free survival, as also noted on multivariate analysis. A significant independent improvement in the definition of risk of progression was achieved by combining miR-182 expression with Gleason score (p <0.0001). miR-187 detection in urine provided an independent predictive value for positive biopsy. A prediction model including serum prostate specific antigen, urine PCA3 and miR-187 provided 88.6% sensitivity and 50% specificity (AUC 0.711, p = 0.001). CONCLUSIONS Results show that miR-182 and 187 are promising biomarkers for prostate cancer prognosis to identify patients at risk for progression and for diagnosis to improve the predictive capability of existing biomarkers.

Late Oncological Occurrences Following Radical Cystectomy in Patients with Bladder Cancer

PURPOSE To evaluate the prognoses and predictive factors of late oncological occurrences and its impact on follow-up strategy in patients with bladder tumours treated with radical cystectomy. MATERIALS AND METHODS Late oncological occurrences were considered when they took place after three years from cystectomy or when early recurrence was controlled with therapy and patients developed recurrence again after a three-year disease-free interval. Univariate and multivariate analysis of predictive factors for late oncological occurrences were carried out on 215 patients at risk of late oncological recurrences. RESULTS Among 357 patients treated with cystectomy, 163 (45.6%) relapsed, 149 (41.7%) of them as early recurrence and 17 (4.7%) were considered as late oncological events. This incidence increased up to 8% when patients at risk were considered. Three patients with early recurrence reached a complete response after treatment and relapsed again as late recurrences. Distant metastases and local recurrence represented 78.5% of early recurrence as opposed to 11.7% in late oncological occurrences, whereas, extravesical urothelium recurrences represented 8.6% and 70% respectively (p<0.01). Among patients with late oncological occurrences, nine (53%) were disease-free, seven with urothelial recurrence and two of three with lymph-node recurrence whereas only eight (5.6%) patients with early recurrence were free of tumour (p<0.0001). Multiple tumours, prostate involvement and organ-confined tumours in cystectomy specimen were the independent variables for predicting late oncological occurrences in multivariate analysis. CONCLUSIONS Recurrences in the remaining urothelium prevail as the pattern of late oncological occurrences. The prognosis of these events is significantly better than an early recurrence. Patients at risk of late oncological occurrences are those with multiple tumours, prostate involvement and with organ-confined tumours in cystectomy specimen. After three years from cystectomy, the follow-up schedule of these patients be limited to performing an annual CT-scan and urinary cytology to detect essentially upper urinary tract recurrence and extrapelvic lymph-nodal recurrence. Afterwards an annual intravenous urography might replace to CT-scan since lymph-nodal involvement was not detected.

Feasibility of Radical Transurethral Resection as Monotherapy for Selected Patients With Muscle Invasive Bladder Cancer

PURPOSE We proved the feasibility of radical transurethral bladder tumor resection in selected patients with muscle invasive bladder cancer with a minimum followup of more than 15 years and investigated the impact of patient age on survival. A followup schedule was developed based on progression and recurrence during this period. MATERIALS AND METHODS A phase II nonrandomized trial was designed including patients with muscle invasive bladder cancer with negative biopsies of tumor bed who were apparently healthy after undergoing complete transurethral bladder tumor resection. Patients with positive biopsies, or with macroscopically residual tumor, hydronephrosis or metastasis were excluded from study. In this trial 133 patients fulfilled the inclusion criteria and had a minimum followup of more than 15 years. RESULTS Cancer specific survival was 81.9%, 79.5% and 76.7%, and progression-free survival with bladder preservation was 75.5%, 64.9% and 57.8% at 5, 10 and 15 years, respectively. Patient age had a negative impact on overall survival on univariate (HR 0.842, p = 0.049) and multivariate analyses (HR 1.062, p = 0.000), and according to median and quartile age stratifications (p = 0.000 and p = 0.000, respectively). However, age did not have a negative impact on cancer specific survival even when following the same stratifications. Although progression and recurrence were concentrated during the first 3 years (70% and 65%, respectively), both steadily increased afterward. A followup schedule was developed according to this sequence of events. CONCLUSIONS Radical transurethral bladder tumor resection is a reliable therapeutic approach for patients with muscle invasive bladder cancer after complete tumor resection and with negative biopsies of the tumor bed. These results are consistent in all age ranges.

Editorial Comment on: Bladder Preservation in Selected Patients with Muscle-Invasive Bladder Cancer by Complete Transurethral Resection of the Bladder Plus Systemic Chemotherapy: Long-Term Follow-up of a Phase 2 Nonrandomized Comparative Trial with Radical Cystectomy

BACKGROUND Many phase 2 bladder-sparing programmes using transurethral resection of the bladder (TURB) plus chemotherapy or radio-chemotherapy have been undertaken, but some controversies remain. OBJECTIVE To determine the efficacy of complete TURB plus three cycles of cisplatin-based chemotherapy in selected patients with muscle-invasive bladder cancer (MIBC). DESIGN, SETTING, AND PARTICIPANTS A phase 2 nonrandomized trial was designed that included patients with MIBC who underwent complete TURB with positive biopsies of the tumour bed. Patients with negative biopsies of the tumour bed, with macroscopically residual tumour, with hydronephrosis, or with distant metastasis were excluded from this trial. Patients included in this trial were offered three cycles of systemic chemotherapy or radical cystectomy (RC). Clinical response (cR) was denoted by either no tumour or the presence of Ta1-Tis bladder tumour at 3-mo evaluation; clinical non-response (cNR) was denoted by cases of muscle-invasive tumour or distant metastasis. Of 146 patients who entered this trial, 75 choose the bladder-sparing programme and 71 chose RC. MEASUREMENTS At 5 yr and 10 yr, the cancer-specific survival (CSS) rate was 64.5% and 59.8%, respectively, with no significant difference compared to the RC arm (p=0.544). The progression-free survival with bladder preserved was 52.6% and 34.5%, respectively. In multivariate analysis, cR was the only predictive factor for survival (p=0.001) and bladder preservation (p=0.000). RESULTS AND LIMITATIONS This was not a randomized trial, and patients were included over 16 yr. However, no modifications were made to the therapy schedule except from chemotherapy schemes considered standard at the time. CONCLUSIONS Patients with microscopic residual cancer after complete TURB seem to be good candidates for the bladder-sparing programme using three cycles of systemic chemotherapy, with CSS comparable to RC.

The optimum timing of radical cystectomy for patients with recurrent high‐risk superficial bladder tumour

To establish the optimum time of radical cystectomy (RC) for patients with recurrent high‐risk superficial bladder tumours after the failure of intravesical therapy.