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Bladder-sparing treatment of invasive bladder cancer.

BACKGROUND: Radical cystectomy with pelvic lymph node dissection is the standard treatment for patients with invasive bladder cancer. However, many alternative techniques to spare the bladder have been investigated. METHODS: We review the experience reported in the literature on bladder-sparing techniques, including transurethral resection, chemotherapy, and radiation for muscle-invasive disease. RESULTS: Most comparative studies indicate that local recurrence and survival outcomes for bladder-sparing approaches are inferior to those from radical cystectomy to control muscle-invasive bladder cancer. CONCLUSIONS: Although molecular biologic techniques may have the capacity to identify a subgroup who may benefit from a bladder-sparing approach, cystectomy is normally required for optimal results.

Antineoplastic Agents↗

Association of cyclooxygenase-2 immunoreactivity with tumor recurrence and disease progression in superficial urothelial bladder cancer.

AIMS AND BACKGROUND: The main characteristic of urothelial bladder cancer is a clear predisposition to recurrence and disease progression. The aim of this study was to assess the possible relationship between cyclooxygenase-2 (COX-2) immunoreactivity in superficial urothelial bladder carcinoma and tumor grade, stage, number of recurrences and clinical disease progression. METHODS: In this prospective study 70 consecutive patients who underwent transurethral resection for superficial urothelial bladder cancer were included. Tumor slides were immunohistochemically stained for COX-2, and COX-2 immunoreactivity in tumor and inflammatory stromal cells was categorized as negative or mildly, moderately or strongly positive. Patients were followed up for 2 years, and during this period the possible association of COX-2 immunoreactivity with tumor stage and grade, number of recurrences and progression of disease was evaluated. RESULTS: COX-2 immunoreactivity in tumor cells was found in 57 (81.4%) patients and did not correlate with tumor grade, stage of disease, number of recurrences, and progression of disease. COX-2 immunoreactivity in inflammatory cells was found in 16 of the 57 patients with COX-2 positive tumors, and was significantly related to the number of recurrences, time to appearance of the first recurrence, and disease progression. CONCLUSIONS: COX-2 immunoreactivity in inflammatory stromal cells adjacent to the COX-2-positive tumor might be useful in clinical practice for selection of patients with a high risk of tumor recurrence and disease progression.

Adult↗

[Assessment of 8-hydroxy-2'-deoxyguanosine concentrations in bladder cancer patients treated with intravesical BCG instillation].

UNLABELLED: Increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentration has been proposed as reliable marker of the oxidative DNA damage, and prognostication of urological carcinogenesis, particularly in bladder cancer. Widely accepted method of treatment in early stages of bladder cancer is transurethral electro resection (TURN). Intravesical bacillus Calmette-Guerin instillation is considered to be the therapeutic agent for superficial transitional cell carcinoma (TCC) of the bladder and has been established as standard therapy in the patients. The aim of the study was to test the concentration of 8-OHdG in urine in patients with bladder cancer and the effect of TURN and BCG therapy on the 8-OHdG value. MATERIAL AND METHODS: We tested 12 patients (3 female and 9 male) with superficial bladder cancer and 31 healthy controls. Urine for the examination was drawn in 4 time points: before and 2 weeks after TURN treatment, then 6 weeks after 6 intravesical instillations of BCG (Onko BCG--BIO MED Lublin) by Morales and 12 weeks after TURN. 8-OHdG concentration in urine was tested using ELISA commercial kit (OXIS health) and the values of 8-OHdG are expressed as ng/ml of urine. RESULTS: Patients with superficial bladder cancer had 16.89 ng/ml of 8-OHdG in urine before the TURN procedure. The value was significantly (p< 0.005) higher then 12.98 ng/ml noted in healthy controls. 2 weeks after the procedure the 8-OHdG level decreased to 13.36 ng/ml. After 6 weeks of repeated 6 intravesical instillations of the BCG the concentration of 8-OHdG dropped to 10.91 ng/ml (p<0.005) and returned to the value 13.28 ng/ml after the next 4 weeks. CONCLUSIONS: Patients with bladder cancer have significantly increased concentration of 8-OHdG in urine compared to controls. 8 week combine therapy with TURN and BCG resulted in a significant decrease in 8-OHdG concentration in urine The beneficial effect of BCG instillations seems to result from strengthening of the antioxidative DNA protection.

8-Hydroxy-2'-Deoxyguanosine↗

[Endoscopic ethanol injection treatment for bladder cancer].

One invasive and 4 superficial bladder cancers were treated by local injection of absolute ethanol through an endoscope. With the patient placed in the lithotomy position, an endoscope was introduced after mucosal anesthesia with xylocaine jelly. According to the usual manner of retrograde catheterization, a 23G syringe needle attached to a 5F ureteral catheter was advanced into the base of the tumor and through the needle absolute ethanol was injected. This treatment is characterized by endoscopic delivery of ethanol as with sclerotherapy for esophageal varices to obtain a potent necrotizing effect as achieved by transcatheter embolization of ethanol for the treatment of renal cell carcinoma. As a rule, this technique does not require any anesthesia other than mucosal anesthesia with xylocaine jelly and can be done repeatedly and very easily, thus having a high cost effectiveness. This treatment serves as a good palliative therapy for invasive bladder cancers, because of its rapid achievement of hemostasis and reduction of the tumor masses. Furthermore, this treatment is just as effective as standard transurethral resections to eradicate superficial bladder cancer, even though the treatment may have to be repeated.

Administration, Intravesical↗

[Urinary bladder transitional cell carcinoma with trophoblastic differentiation].

Transitional cell carcinoma (TCC) with trophoblastic differentiation (TD) is a newly recognized variant of urothelial cancer which produces placental proteins, predominantly beta-human chorionic gonadotropin (HCG). It has a poor prognosis. About 210 cases were described, mostly from North America, Europe and Japan. This is the first report of TCC TD in a resident of Israel's upper Galilee. A 69-year-old man whose urinary papillary bladder tumor was established cystoscopically, refused treatment and stopped follow-up. 3.5 years after his last visit, he returned and cytologic examination revealed malignant urothelial cells, while intravenous pyelography disclosed a urinary bladder defect. Cystoscopy showed numerous papillary masses dispersed over the bladder mucosa, which were resected transurethrally. Histopathologic examination revealed TCC grade III, stage A. Tumor cells were immunopositive for beta-HCG and human placental lactogen. 4 transurethral resections of large masses were performed within 2 months. Pulmonary metastases developed and the patient died 4 years after the detection of the urinary bladder tumor.

Aged↗

Diagnosis of bladder cancer by analysis of urinary fibronectin.

OBJECTIVES: To evaluate the diagnostic efficacy of the analysis of fibronectin in the urine samples of patients with bladder cancer. METHODS: The study included 123 subjects: one group of 68 patients with bladder cancer confirmed by transurethral resection; a second group of 10 patients with benign urologic disease, and a third group of 45 healthy subjects. We carried out the analysis of bladder tumor fibronectin (BTF), cytology, and creatinine in urine, and calculated the BTF/creatinine (BTF/CREA) ratio. For the determination of BTF, we used a solid-phase chemoluminescent immunometric test. RESULTS: The receiver operating characteristic curves showed an optimal cutoff point of 25.6 microg/L and 36.9 microg/g for BTF and the BTF/CREA ratio, respectively, with a sensitivity of 78% and 75%, respectively, and specificity of 80% for both. The sensitivity of urinary cytology was only 55%, but the specificity was 100%. The patients with bladder cancer had significantly greater levels of BTF and the BTF/CREA ratio than did the healthy subjects (P <0.001) and, in the case of BTF without correcting for creatinine, than did the patients with benign urologic disease (P <0.05). We also found significant differences in the levels of BTF and the BTF/CREA ratio among tumor stages, degree of differentiation, tumor size, multifocal nature, and macroscopic appearance. CONCLUSIONS: Determination of fibronectin could be a useful test in the diagnosis of bladder tumors. The association between BTF and all known prognostic parameters implies its potential value in making therapeutic decisions. Nevertheless, the utility of BTF needs to be studied in a wider way in the presence of other pathologic features concurrent with bladder cancer.

Biomarkers, Tumor↗

Intravesical interleukin-2 in T1 papillary bladder carcinoma: regression of marker lesion in 8 of 10 patients.

PURPOSE: We evaluate the therapeutic effect of intravesical interleukin-2 (IL-2) on T1 papillary bladder carcinoma after incomplete transurethral resection. MATERIALS AND METHODS: After incomplete transurethral resection we treated 10 patients in whom the marker lesion was left in place with 3 x 10(6) Chiron units IL-2 in 50 ml. saline plus 0.1% human serum albumin. The solution remained in the bladder for 2 hours and it was instilled on 5 consecutive days. The effect of IL-2 treatment on the marker lesion was evaluated by cystoscopy and repeat biopsy of the marker site 2 months after treatment. In addition, the effect on the recurrence of bladder tumors was studied. RESULTS: At 2 months 8 of the 10 marker lesions (80%) had completely regressed and there were no tumor cells on repeat biopsy. Four patients remained tumor-free after 30 to 54 months. We noted no toxic effects. In 1 patient with a 7-year history of bladder cancer the marker was only partially regressed after 2 months. After removal of the marker this patient remained tumor-free at a followup of 54 months. CONCLUSIONS: To our knowledge this report represents the first study of the effect of IL-2 on marker lesions left in place after transurethral resection. The results indicate that IL-2 instillations are feasible, and the combination of transurethral resection and IL-2 instillation may have a powerful antitumor effect. The therapeutic effects may not simply be due to intravesical IL-2, because previous transurethral resection probably caused some influx of infiltrating cells and the marker may have had tumor associated antigens. Consequently these effects may be due to the interaction of tumor associated antigens, infiltrating cells and IL-2.

Administration, Intravesical↗

[The use of BCG vaccine for preventing recurrences of superficial bladder cancer].

Responses to immunoprophylaxis of superficial bladder cancer in 94 post-transurethral resection patients were analyzed. Once-a-week intravesicular instillations of BCG vaccine in a dose 100 mg diluted in 50 ml of physiological solution were initiated 30 days after transurethral resection. The main course of therapy comprised 8 instillations made outpatiently. Subsequently the patients underwent a maintenance immunoprophylactic course once a month in the same dose (100 mg) for a year since transurethral resection. 3 years after therapy gave rise to the tumor recurrences in 12 (12.8%) out of 94 patients contrary to 37 (43.0%) patients out of 86 patients. BCG is able to prevent recurrences of superficial bladder cancer subjected to transurethral resection in the majority of patients.

Adjuvants, Immunologic↗

Acute urinary retention: defining the need and timing for pressure-flow studies.

OBJECTIVE: To investigate the utility of "late" pressure-flow studies in predicting the outcome of prostatectomy for acute urinary retention. PATIENTS AND METHODS: Fifty-eight patients with acute urinary retention were prospectively assessed using the International Prostate Symptom Score and pressure-flow studies at a median (range) of 24 (13-60) days after the episode of retention, and before transurethral resection of the prostate. Bladder outlet obstruction and bladder contractility were graded using a modified adaptation of Schäfer's passive urethral linear resistance relation. RESULTS: Fifty-six (97%) patients generated a voluntary detrusor contraction, with a mean (range) detrusor pressure at maximum flow of 72.7 (5-144) cmH2O, and 43 (75%) patients were deemed to be obstructed. Eight (16%) patients failed to void after prostatectomy and required clean intermittent catheterization. There were statistically significant differences between successful and unsuccessful patients in mean (SD) age, at 66.30 (6.9) vs 78.8 (2.6) years (P = 0.001), detrusor instability (49% vs 0%, P = 0.01), inability to void during pressure study (8% vs 75%, P = 0.001), and maximal detrusor pressure in the voiding phase, at 80 (36.0) vs 19 (11.2) cmH2O (P = 0.001). CONCLUSIONS: In patients with acute urinary retention, pressure-flow studies undertaken after a period of adequate bladder rest (> 3 weeks) are useful in predicting the surgical outcome. Old age, absence of bladder instability, inability to void during the pressure-flow study and a maximal detrusor pressure of < 20 cmH2O are associated with a poor outcome after prostatectomy.

Acute Disease↗

Bladder preservation by combined modality therapy for invasive bladder cancer.

PURPOSE: To update the efficacy of a selective multimodality bladder-preserving approach by transurethral resection (TURBT), systemic chemotherapy, and radiation therapy. PATIENTS AND METHODS: From 1986 through 1993, 106 patients with muscle-invading clinical stage T2 to T4a,Nx,M0 bladder cancer were treated with induction by maximal TURBT and two cycles of chemotherapy (methotrexate, cisplatin, vinblastine [MCV]) followed by 39.6-Gy pelvic irradiation with concomitant cisplatin. Patients with a negative postinduction therapy tumor site biopsy and cytology (a T0 response, 70 patients) plus those with less than a T0 response but medically unfit for cystectomy (six patients), received consolidative chemoradiation to a total of 64.8 Gy. Surgical candidates with less than a T0 response (13 patients) and patients who could not tolerate the chemoradiation (six patients) went to immediate cystectomy. The median follow-up duration is 4.4 years. RESULTS: The 5-year actuarial overall survival and disease-specific survival rates of all patients are 52% and 60%, respectively. For clinical stage T2 patients, the actuarial overall survival rate is 63%, and for T3-4, 45%. Thirty-six patients (34%) underwent cystectomy, all with evidence of tumor activity, including 17 with an invasive recurrence. The 5-year overall survival rate with an intact functioning bladder is 43%. Among 76 patients who completed bladder-preserving therapy, the 5-year rate of freedom from an invasive bladder relapse is 79%. No patient required cystectomy for treatment-related bladder morbidity. CONCLUSION: Combined modality therapy with TURBT, chemotherapy, radiation, and selection for organ-conservation by response has a 52% overall survival rate. This result is similar to cystectomy-based studies for patients of similar age and clinical stages. The majority of the long-term survivors retain fully functional bladders.

Adult↗

[Conservative treatment of high-risk (T1G3) transitional carcinoma].

OBJECTIVE: This study evaluates the outcome of patients (pts) with primary T1G3 bladder cancer treated by transurethral resection (TUR) alone or followed by intravesical prophylaxis (BCG/Doxorubicin). Cistectomy was considered at disease progression. METHODS: Between 1/89 and 5/95 thirty-one pts with primary T1G3 bladder cancer were treated by TUR, in 24 followed by intravesical prophylaxis (13 with BCG, 11 with Doxorubicin). 7 pts had only TUR. RESULTS: At 42 months median follow up 45.2% pts (14/31) are disease free. The recurrence rate was 25.8% (8/31) and progression of disease was seen in 29.0% (9/31); mortality rate was 22.6% (7/31). In 13/31 pts treated by TUR + BCG 53.8% pts (7/13) are disease free. The recurrance rate was 23.1% (3/13) and progression of disease was seen in 23.1% (3/13) of cases; mortality rate was 23.1% (3/13). In 11/31 pts treated by TUR+Doxorubicin 54.5% pts (6/11) are disease free. The recurrance rate was 18.2% (2/11), progression of disease was seen in 27.3% (3/11) of cases of mortality rate of 9.1% (1/11). In 7/31 pts treated by TUR alone 14.3% pts (1/7) are disease free. The recurrance rate was 42.9% (3/7) and progression of disease was seen in 42.9% (3/7) of cases and mortality rate of 42.9% (3/7). Cistectomy was considered in 4 pts (3 for disease progression and 1 because of no disease free interval). The other pts with progression were not treated surgically because of their poor performance status. CONCLUSION: At a 42 months median follow up 77.4% pts (24/31) are alive (83.3% pts treated by TUR+intravesical prophylaxis). 64.5% pts (20/31) still have their bladder (66.6% pts treated by TUR+intravesical prophylaxis (16/24). We did not find a significative difference between prophylaxis with immunotherapy or chemotherapy. In conclusion we believe that the conservative management of high risk bladder transitional cell carcinoma T1G3 is feasible and allow us to plan cistectomy only in pts with progression or recurrance with no free interval without losing survival.

Administration, Intravesical↗

Study of cellular DNA content by flow cytometry in primary bladder carcinomas. Significance of monoclonal and multiclonal varieties of DNA aneuploidy.

A prospective study of cellular DNA content by flow cytometry was performed on a nonconsecutive series of 67 patients undergoing diagnostic and/or therapeutic transurethral resection for primary urothelial bladder carcinoma. DNA-aneuploidy was present in 82% of the cases (55/67), while multiclonality was found in 45% of the DNA-aneuploid cases (25/55). DNA-ploidy was much more strictly correlated with histological grading (p less than 0.005) than with papillary or non-papillary growth pattern (p less than 0.05) or T staging (p less than 0.05). Of 26 patients with a minimum follow-up of 24 months, 100% (6/6) of cases with DNA-diploid neoplasias showed no signs of disease relapse, versus 10% (2/20) of those with DNA-aneuploid neoplasias (p less than 0.001). Furthermore, tumoral progression occurred in 10 of 20 cases (50%) with aneuploid DNA content. In this latter group of 10 cases a multiclonal DNA-aneuploid pattern was found, with a significant difference (p less than 0.001).

Aged↗

[Comparative study between cystoscopy, urinary cytology, NMP-22 and a new method, bladder chek, in the follow-up of superficial bladder cell carcinoma].

OBJECTIVE: The goal of this work tries to evaluate the utility of the qualitative determination of NMP-22 in the evaluation of the superficial bladder carcinoma in asymptomatic patients, comparing it with its quantitative determination, the cytology and the cystoscopy. MATERIALS AND METHODS: A simple of urine just voided was taken in 88 asymptomatic patient follow-up for superficial bladder cell carcinoma. This dose was distributed in 3 parts, for performed cytology, for determination of NMP-22, and 4 drops of the third part are added to device bladder chek. Later, we performed cystoscopy and transurethral resection in patients with a suspicion of bladder cancer. RESULTS: 26 patients had tumor relapse and 62 patients were free of disease. The sensitivity for the bladder chek was of 28%, 34.62% for NMP-22, 34.62% for cytology and 100% for cystoscopy. The specificity was of 93.55%, 80.33%, 87.10% and 87.10% respectively. The sensitivity by degree was 25 in G1, 28.57 in G2 and 50 in G3 for Bladder chek; 29.41, 42.86 and 50 for NMP-22; 23.53, 71.43 and 0 for cytology. The sensitivity by stages was 27.7 in Ta-1 and 50 in T2 for Bladder chek; 34.78 and 50 for NMP-22; 39.13 and 0 for the cytology. CONCLUSIONS: The low sensitivity of bladder chek invalidates it like alternative method to the cystoscopy in the follow-up of the superficial asymptomatic bladder cell carcinoma.

Carcinoma, Transitional Cell↗

[Upper urinary tract tumors following bladder cancer].

We treated in total 795 patients with primary transitional cell carcinoma of the urinary bladder between April, 1964 and December, 1988. Eighteen patients of them had upper urothelial cancer during the follow-up period. Thirteen of the 18 patients had received transurethral resection for the initial bladder cancer, while 3 total cystectomy and 2 segmental resection. The over-all incidence of bladder cancer patients who subsequently developed upper urinary tract tumors was 2.3 per cent. The interval between initial treatment of the bladder cancer and treatment for the upper urinary tract tumor ranged from 2 to 74 months (median 20 months). The five-year survival rate after treatment for the upper urinary tract tumor was 31.7 per cent. We conclude that the following are high risk patients for development of upper urinary tract recurrences: 1) patients with bladder cancer near orifices, 2) patients with recurrent bladder cancer under bladder preserving treatment for a long time, 3) patients with G2 multifocal bladder cancer.

Aged↗

Update on the Dutch Cooperative Trial: mitomycin versus bacillus Calmette-Guérin-Tice versus bacillus Calmette-Guérin RIVM in the treatment of patients with pTA-pT1 papillary carcinoma and carcinoma in situ of the urinary bladder. Dutch South East Cooperative Urological Group.

Prophylactic intravesical treatment with chemotherapeutic agents or one of the different strains of the immunomodulator bacillus Calmette-Guérin (BCG) reduces tumor recurrence and may prevent progression after transurethral resection (TUR) of superficial bladder cancer. Clinical and pathological prognostic factors are used to categorize different groups at risk for disease recurrence and progression. Solitary low-grade (G1, 2A), low-stage (pTa) tumors have less than a 5% risk of progression, while pT1 G3 tumors with concomitant carcinoma in situ (CIS) have a considerably higher risk of progression and metastases. Thus, prospective clinical trials should consider the different risks associated with different prognostic groups and stratify patients accordingly. The Dutch Cooperative Trial evaluated mitomycin versus BCG-Tice versus BCG-RIVM in 469 patients with pTA/pT1 carcinoma and CIS of the urinary bladder after TUR. Of 437 evaluable patients, 50 had CIS, 254 had pTA tumors, and 133 had pT1 tumors. No statistical differences were observed in toxicity between the two strains of BCG, but local and systemic side effects were more frequent in the BCG groups versus the mitomycin group. No differences in response rate were observed between the 3 treatment groups in patients with CIS. A statistically significant difference in favor of mitomycin was seen, however, in patients with papillary tumors. Mitomycin and BCG-RIVM were equally effective, and mitomycin proved significantly more effective than BCG-Tice. No significant difference in efficacy was observed between the two strains of BCG. Disease recurrence during the study in patients with papillary tumors was seen in 43% of mitomycin-treated patients, 64% of the BCG-Tice group, and 46% of patients treated with BCG-Rivm. However, a subgroup analysis for time to first recurrence for pTa versus pT1 and for grade 1 and 2 versus grade 3 papillary tumors showed no statistically significant between-group difference. Further studies comparing identical regimens, doses, and patient groups are needed to define more clearly which patient groups and tumors are more likely to respond to intravesical therapy.

Adjuvants, Immunologic↗

Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy?

PURPOSE: In this retrospective nonrandomized study we compared the long-term outcome in patients with newly diagnosed stage T1G3 bladder cancer treated with transurethral resection and bacillus Calmette-Guerin or immediate cystectomy. MATERIALS AND METHODS: Of 121 patients with a median age of 67 years (range 36 to 88) diagnosed with primary T1G3 bladder cancer between 1976 and 1999, 92 were treated by transureteral resection with additional intravesical bacillus Calmette-Guerin and 29 were treated with immediate cystectomy. RESULTS: Of the 92 patients treated with an organ preserving approach 29 remained disease-free, local recurrence developed in 33 (36%) and progression developed in 30 (33%) at a median followup of 6.9 years (range 0.6 to 16.5). Of these 92 patients 27 (29%) underwent deferred cystectomy at a median of 12.9 months (range 4.8 to 136), of whom 10 (37%) with a median postoperative followup of 19 months (range 2 to 173) died of progressive disease with a median survival of 13 months (range 3 to 34) after cystectomy. The majority of patients who died of progressive disease refused cystectomy, were referred too late for cystectomy, were inoperable or had upper urinary tract disease. Six of the 29 patients (21%) undergoing immediate cystectomy had progression at a median of 13.2 months (range 5.5 to 37). Overall and tumor specific survival at 5 years in patients treated with an organ preserving approach was 69% and 80%, and in those treated with immediate cystectomy it was 54% and 69%, respectively. CONCLUSIONS: The results of this analysis demonstrate that the concept of an organ preserving approach is acceptable and spares the bladder in approximately half of the patients with primary T1G3 bladder cancer. Of the patients 30% require deferred cystectomy, making meticulous, close followup mandatory.

Adjuvants, Immunologic↗

Bladder cancer.

Bladder cancer is the fourth most common cancer in England and Wales. The most common presenting symptom is macroscopic haematuria. The management options for superficial and invasive bladder cancer depend on the stage at presentation. Most superficial bladder cancers are managed by transurethral resection and cytoscopic follow-up. The prognosis for patients with invasive bladder cancer is less good. The role of chemical, radiotherapeutic and surgical intervention are discussed.

Antineoplastic Agents↗