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Context: The therapeutic strategy in intermediate risk (IR) non-muscle invasive bladder cancer (NMIBC) recurring after intravesical therapy (IT) is not well defined. Most patients are usually retreated by Bacillus Calmette-Guerin (BCG). Aims: To evaluate the efficacy of intravesical chemotherapy (ICH) given at recurrence after the first cycle of ICH in IR-NMIBC recurring 6 months or later. Settings and Design: Retrospective analysis of the efficacy of ICH given after previous IT. Materials and Methods: The clinical files of IR-NMIBC patients recurring later than 6 months after transurethral resection (TUR) and IT and retreated by IT were reviewed. The patients should be at intermediate risk both initially and at the first recurrence. BCG should have been given at full dose. Cytology and cystoscopy were performed 3 monthly for 2 years and then 6 monthly. Statistical Analysis: The RFS was estimated by the Kaplan-Meier method and the differences between treatment groups were compared by log-rank test. Mann Whitney U-test was used to compare the parameters′ distribution for median time to recurrence. Multivariate Cox proportional hazards models were used. Results: The study included 179 patients. The first IT was ICH in 146 (81.6%) and BCG in 33 (18.4%), re-IT was ICH in 112 (62.6%) and BCG in 67 (37.4%) patients. Median time to recurrence was 18 and 16 months after first and second IT (P = 0.32). At 3 years, 24 (35.8%) and 49 (43.8%) patients recurred after BCG and ICH, respectively (P = 0.90). No difference in RFS was found between BCG and ICH given after a first cycle of ICH (P = 0.23). Conclusions: Re-treatment with ICH could represent a legitimate option to BCG in patients harboring IR-NMIBC recurring after TUR and previous ICH. Prospective trials are needed.

OBJECTIVES: To evaluate a highly selected population of patients affected by T1G3 bladder transitional cell carcinoma (TCCB) treated by transurethral resection (TUR) and adjuvant intravesical chemotherapy. MATERIALS AND METHODS: Between January 1976 and April 1999, 137 patients with T1G3 TCCB were treated by TUR plus intravesical chemotherapy. Particularly, a sequential combination of mitomycin C (MMC) and epirubicin (EPI) was adopted in 91 patients (66.4%). The main exclusion criteria were concomitant or previous Tis, previous T1G3 TCCB, tumor size greater than 3 centimeters and number of tumors more than 3. TUR was repeated if a superficial tumor recurred. Patients went off study if Tis, recurrent T1G3 or invasive tumor were detected during treatment or thereafter. Adjuvant therapy, recurrence and progression were considered in multivariate analysis regarding recurrence, progression and survival respectively. RESULTS: Observation period was up to 240 months with a minimum of 2 years in 112 patients (82%). Seventy patients (51%) recurred. The recurring tumor was again a T1G3 in 22 (16%) patients. Thirteen patients (9.5%) progressed. The 5-year progression-free survival rate was 90%. Median progression-free survival was 149 months. Twenty-two patients (16%) died, 9 (6.6%) of whom due to bladder cancer. Median overall survival was 155 months. The 3- and 5-year disease-free overall survival rates were 89% and 80% respectively. Ten cystectomies (7.3%) were performed. In conclusion, 123 patients (90%) maintained their intact bladder with a mean disease-free overall survival of 104 months. The sequential combination of MMC and EPI adjuvant therapy resulted more effective to be than single drug chemotherapy on recurrence rate (p=0.0021) but had no impact upon progression (p=0.127) and specific survival (p=0.163). Progression (p

Objective To study the effect of smoking status at diagnosis on recurrence in intermediate-risk non–muscle-invasive bladder carcinoma treated by transurethral resection (TUR) of the bladder and early intravesical chemotherapy. Methods Tumor characteristics and smoking status were recorded in 395 patients entered in a randomized multicenter trial comparing 2 different schedules of early intravesical chemotherapy. All patients received intravesical epirubicin (80 mg/50 mL) within 6 hours after TUR, followed by 5 more weekly instillations with (arm B) or without (arm A) monthly instillations for 1 year. Smoking habit was investigated at diagnosis through a structured questionnaire. Multivariate statistical analysis was performed to study the recurrence-free survival (RFS) and the recurrence-free rate (RFR) in relation to smoking status. Results Ninety-seven (24.6%) patients never smoked and 298 (75.4%) were smokers. At a median follow-up of 48 months, 117 patients (29.6%) recurred, 63 in arm A and 54 in arm B (P = .43). Ten patients (2.5%) progressed. The 3-year RFS, RFR, and median time to first recurrence of smokers and patients who never smoked were 64.0% and 71.3% (P = .08), 69.1% and 74.2% (P = .16), and 13.6 and 14.2 months (P = .27), respectively. The multivariate analysis identified previous history (P = .01) and smoking status (P = .04) as the main prognostic factors for recurrence in these patients. No difference in recurrence risk at 3 years was detected between current and former smokers. Conclusion In intermediate-risk non–muscle-invasive bladder carcinoma treated by early intravesical chemotherapy, smoking status influences significantly the 3-year RFS. No difference was detected between current and former smokers.

BACKGROUND: Tamoxifen (TAM) has been shown to be active against the bicalutamide-induced breast events (BEs) gynecomastia, and breast pain in patients with prostate cancer (PC). Optimal doses and schedules are not yet established. Debate still exists about whether prophylaxis with TAM is more effective than treatment of BEs when diagnosed. The results of a randomized study comparing TAM prophylaxis vs. TAM therapy are presented. METHODS: One hundred seventy-six patients with prostate cancer (PC) who were candidates for bicalutamide monotherapy were randomized to receive TAM 20 mg daily orally within 1 month from the onset of BEs (arm A) vs. TAM 10 mg daily starting simultaneously with bicalutamide (arm B). TAM was administered for up to 1 year. BEs were evaluated by a self-administered visual analogue scale. Neither ultrasonography nor calipers were used to measure the degree of gynecomastia. RESULTS: In arm A, BEs showed a prevalence, increasing with time up to 78.3%. After therapy with TAM they persisted in 27.7% of cases. Two patients (3%) interrupted TAM therapy because of dizziness, and 3 patients (4%) interrupted bicalutamide therapy because of painful gynecomastia. In arm B, the prevalence of BEs was 35% after 12 months of therapy. The difference in BEs between the 2 arms was statistically significant (P < .0001). The differences in prevalence of gynecomastia and breast pain between the 2 arms both favored TAM prophylaxis (P < .0001 and P < .001, respectively). Up to 35% of patients had BEs of low intensity, never requiring bicalutamide withdrawal. Two patients (3%) interrupted the treatment because of gastrointestinal intolerance. No difference emerged between the 2 arms in terms of prostate-specific antigen (PSA) response, plasma testosterone levels, and tumor progression. CONCLUSION: Bicalutamide-induced BEs can be prevented to a significant degree by prophylaxis with TAM 10 mg/day or effectively treated with TAM therapy 20 mg/day. Persisting BEs are of higher intensity after therapy than after prophylaxis.

Objectives: To investigate the safety and efficacy in terms of PSA response of a low-dose oral combination of estramustine phosphate (EMP) and etoposide (VP16) in hormone- refractory prostate cancer (HRPC) patients. Well-tolerated outpatient chemotherapy regimens for patients unfit and/or unwilling to be admitted to hospital are needed. Methods: Fifty-six HRPC patients with metastatic disease (median age 75 years) were randomized between arm A (daily oral EMP 10 mg/kg, in 3 doses) and arm B (28-day cycle with low-dose EMP 3 mg/kg once daily plus VP16 25 mg/m2 once daily on days 1 through 14). Baseline characteristics between the two groups were similar. LHRH therapy was maintained. Anti- androgen was stopped 1 month before entry. Results: The low-dose combination was better tolerated, with a significant advantage in terms of time to treatment interruption for any reason (p = 0.01) or toxicity (6 vs. 12 months, p = 0.02). A trend in favour of arm B was evident in terms of PSA reduction (41.4 vs. 15%), performance status and pain improvement. Hospital admission due to toxicity was never required for arm B patients and there were no treatment-related deaths. Conclusions: Low-dose oral combination of EMP and VP16 might represent a treatment option for patients unfit for i.v. chemotherapy. This regimen requires minimal toxicity monitoring when administered at home for prolonged periods.

Microscopic foci of prostatitis may induce prostate-specific antigen (PSA) increase. PSA reduction after antibiotics might identify those patients in whom biopsy can be avoided. Ninety-nine patients received ciprofloxacin for 3 weeks, of whom 59 showed PSA reduction. Histology detected small foci of prostatitis in 65% of cases. Carcinoma was found in 40 and 20.3% of patients with unchanged or decreased PSA, respectively (P=0.03). No cancer was detected if PSA decreased below 4 ng/ml or more than 70%. Biopsy can be postponed, with a low risk of missing a cancer, if PSA decreases more than 70% or below 4 ng/ml.

Purpose: In the absence of Tis tumor we assessed whether history and multiplicity have a detrimental effect on conservative treatment in carefully selected patients with T1G3 bladder carcinoma. Materials and Methods: Between January 1976 and December 1999, 165 select patients with T1G3 bladder tumors were conservatively treated with transurethral resection plus adjuvant intravesical therapy. Patients with concomitant or previous Tis, previous T1G3, tumor size greater than 3 cm and more than 3 lesions were excluded from analysis. Repeat transurethral resection was not routinely performed. However, cytology had to be negative for atypia before the start of adjuvant intravesical therapy. Results: Recurrence-free survival at 1, 3 and 5 years was 71.8%, 55.6% and 45%, respectively. Of the cases 14 (8.4%) progressed with a median progression-free survival of 149 months. A total of 23 patients (14%) died. The 5-year recurrencefree survival rate was 52%, 34% and 15% in cases of single and/or primary, multiple and recurrent tumors, respectively. Median overall survival was 144 months. The 5-year disease-free overall survival rate was 85%, 83%, 79% and 69% in cases of primary, single, multiple and recurrent tumors, respectively. An intact bladder was maintained in 137 patients (83%) with a mean disease-free overall survival of 102.7 months. Patients with recurrent and/or multiple T1G3 tumors showed worse survival (p 0.0021 and 0.0142, respectively). Conclusions: History and multiplicity are relevant predictors of survival even in highly selected patients with TIG3 bladder tumors that are conservatively treated. Key Words: carcinoma, transitional cell; survival; chemotherapy, adjuvant; neoplasms, multiple primary; recurrence

Introduction and Objective: Gynaecomastia is a potentially treatment limiting adverse event of antiandrogen monotherapy for prostate cancer. Tamoxifen has shown to be effective in therapy and prophylaxis of gynecomastia and breast pain. However, tamoxifene dosage and treatment duration are not established and debate still exists if prophylaxis is more effective than therapy at the early onset. This randomized study compared the prophylactic activity of tamoxifene at the dose of 10 mg with its therapeutic activity when given at the dose of 20 mg at the early appearance of gynecomastia in patients receiving bicalutamide 150 mg/d for prostate cancer. Methods: Between June 2005 and June 2007, 176 patients (median age 74 years), affected by prostate cancer have been randomized, at the moment of bicalutamide prescription, in to 2 arms according to gynecomastia treatment with tamoxifen. Arm A: Tamoxifen 20 mg/daily given for one year starting at the early onset of gynecomastia (within one month); tamoxifen 10 mg/daily given for one year starting at the prescription of bicalutamide. Routine laboratory exams, testosterone, PSA and follow-up visits were obtained at one month and then 3-monthly. Gynecomastia and breast pain were evaluated by the patients through a self-administered visual analog scale. Moreover, gynecomastia was classified into 4 grades (0-4) by physical examination. Results: At a follow-up between 3 and 24 months, gynecomastia increased in arm A from 34% at 3 months up to 78% after 12 months of bicalutamide therapy. When tamoxifen 20mg was given all patients showed gynecomastia and breast pain reduction, not vanishing, however, in 56% and 34% of cases respectively. Two patients interrupted the treatment after 3 months due to dizziness and 4 (5%) patients did not considered relevant the gynecomastia and did not take the drug. The incidence of gynecomastia and breast pain was significantly reduced (p

Objectives: Well tolerated out-patient regimens for HRPC chemotherapy in elderly patients with geographical difficulties and/or unwilling hospital admission are needed. The aim of the present study was to investigate the safety and efficacy of a low-dose oral combination of estramustine phosphate (EMP) and etoposide (VP16). Patients: Fifty-six HRPC patients, median age 75 years, were randomized between daily EMP (10mg/kg) – arm A, and low-dose EMP (3mg/kg) plus VP16 (25mg/mq) 2 weeks monthly – arm B. Randomization ratio was 2:3. Median PSA was 41.1 ng/ml. Baseline characteristics between the 2 groups were similar. LHRH therapy was maintained. Antiandrogen was stopped one month before entry. Results: Seven patients went off study for protocol violation. Treatment interruption due to toxicity was necessary in 6 patients (30%) of arm A and 5 (17.2%) of arm B. The low dose combination was better tolerated with a significant advantage in terms of time to treatment interruption (any reason) (p=0.01) and time to treatment interruption for toxicity (6 vs 12 months; p=0.02). Hospital admission due to toxicity was never required for arm B patients and there were no treatment-related deaths. PSA reduction of more than 50% was obtained in 3 (15%) and 12 (41.4%) patients of arm A and B respectively. Improvement in PS and pain was observed in 5 (25%) and 13 (44,8%), and in 12 (60%) and 22 (75.8%) patients of arm A and B respectively. Ten patients (50%) of arm A and 15 (51.7%) of arm B progressed with a median time to progression of 3 and 9 months respectively. Median progression free survival and median overall survival were 6 and 15 months (p= 0.02) and 13 and 17 months (p=0.63) respectively. Conclusions: Low-dose oral combination of EMP and VP16 can be safely administered at home for prolonged therapy periods in elderly patients. Symptoms and QoL are improved and time to progression and survival are not different from those obtained by other full dose chemotherapeutic regimens, although accompanied by a lower PSA response. This regimen is better tolerated than full those EMP and might represent a treatment option for patients who can not be submitted to regimens requiring hospital admission.

Objective: The distribution of potential environmental risk factors among patients affected by superficial transitional cell carcinoma of the bladder (TCCB) has been analyzed. Methods: Patients affected by superficial TCCB underwent TUR and early intravesical chemotherapy. Detailed data about age, sex, residence, employment, active and passive cigarette smoking, water resource and hair dye use were centralized. Analysis has been conducted on 474 patients affected by Ta-T1 G1-2 TCCB at medium risk for recurrence. Patients with primary single Ta G1-2, Tis or T1G3 tumors were excluded from the present analysis. Results: Over 80% of the patients lived in urban areas, 22% were employed in industries presumed at risk for bladder cancer, 8% used hair dye and 75% were smokers. Bottled water was the only water resource in 42% of the patients. Employment in industry at risk (p = 0.01) and cigarette smoking (p = 0.04) resulted in being statistically related to tumor multiplicity. Moreover, the period of cigarette smoking was significantly longer in patients with recurrent tumors (p = 0.026). The municipal water supply represented the main water source in never-smokers (p = 0.01) rather than in smokers and in patients harboring T1 rather than Ta tumors (p = 0.03). Conclusions: Employment in industry at risk and cigarette smoking resulted in being related to tumor multiplicity. The length of exposure to cigarette smoking was related to the natural history of the tumor. A drinkable water source emerged as a risk factor in absence of cigarette smoking.

To study GP-170 in superficial bladder cancer at initial diagnosis and at recurrence and to evaluate if intravesical chemoprophylaxis modifies the expression of GP-170 in tumor recurrences. GP-170 was retrospectively assessed in 160 patients affected by primary superficial transitional cell carcinoma of the bladder and followed for up to 10 years. Eighty-four patients (52.5%) recurred after transurethral resection (TUR). Adjuvant intravesical chemotherapy after TUR was adopted in 52 patients. The correlations between GP-170 and G-grade, T-category, risk of recurrence and of progression, and adoption of adjuvant intravesical chemotherapy were investigated. The correlations between variations in grade and stage at recurrence and modifications in GP-170 expression were also studied. No significant correlation between GP-170 expression and G-grade and T-category was found. A significant correlation was detected between GP-170 expression and recurrence (P=0.0383). It showed a biphasic pattern, i.e., tumors that did not express GP-170 had a higher recurrence rate, but high GP-170 levels were also associated with an increasing risk of recurrence. Intravesical chemotherapy did not induce significative variations in GP-170 expression. No correlation was found between progression and GP-170. GP-170 seems to be an independent prognostic factor for recurrence in superficial bladder tumors. A negative GP-170 pattern and high levels of GP-170 are associated with an increasing risk of recurrence but have no impact upon progression. In our experience, GP-170 is neither induced nor modified by intravesical chemotherapy, although it might represent a factor of chemoresistance when strongly expressed.

Introduction and Objective: Adjuvant intravesical chemotherapy or BCG immunotherapy after transurethral resection (TUR) is a standard treatment for non–muscle-invasive transitional cell cancer of the bladder (NMI TCCB) at intermediate risk. Although the clinical value of early intravesical adjuvant chemotherapy is well established, the optimal schedule regimen and the role of maintenance is still debated. Methods: Between May 2002 and August 2003, 577 patients, undergoing TUR for NMI TCCB, were recruited. All patients underwent TUR and early (within 6 hours) intravesical chemotherapy with epirubicin at the dose of 80 mg diluted in 60 ml of saline solution. When histology was available, 95 patients were excluded from the study since they were harbouring T1G3, Tis and single and primary Ta G1-G2 tumors. 482 patients with intermediate risk tumors were randomized according 2 different regimens: arm A: 5 more weekly instillations; arm B: 5 more weekly instillations plus monthly instillations for a total of 16 instillations. All patients were submitted 3-monthly for the first 2-years and then 6-monthly to cytology, cystoscopy and biopsy of every suspicious bladder lesion.. Results: Out of 482 randomized patients, 396 are evaluable for toxicity and 392 for efficacy. The tumours were multiple in 318 patients (66.0%) and recurrent in 192 (39.8%). No difference emerged between the 2 arms in relation to tumors’ characteristics. The median follow-up time was 22 months (range: 3-56). Eighty-two (20.9%) patients recurred at a median time of 9 months from TUR and 4 patients (1%). The incidence of recurrences was 24.4% (47/192) in arm A and 18.5% (35/200) in arm B. No difference emerged between the two arms for recurrence rate at 3 months (p=0.06). Statistical analysis demonstrated an advantage in favour of maintenance in terms of recurrence rate at 6 (p=0.01), 9 (p=0.04) and 12 months (p=0.03) and in terms of recurrence-free interval (p=0.03). No difference for toxicity was detected according to treatment schedule. Conclusions: One-year maintenance significantly reduces the risk of tumour recurrence without enhanced toxicity, in patients with intermediate risk NMI TCCB treated with early epirubicin intravesical chemotherapy followed by 5 weekly instillation.