Renzo Colombo

Multicentric Study Comparing Intravesical Chemotherapy Alone and With Local Microwave Hyperthermia for Prophylaxis of Recurrence of Superficial Transitional Cell Carcinoma

PURPOSE To compare the efficacy and local toxicity of the intravesical instillation of a cytostatic drug versus the same cytostatic agent in combination with local hyperthermia as an adjuvant treatment, after complete transurethral resection (TURB) of superficial transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS The study was designed as a prospective, multicentric, randomized trial. Eighty-three patients suffering from primary or recurrent superficial (Ta-T1) TCC of the bladder, after a complete TURB, were randomly assigned to receive intravesical instillations of mitomycin C (MMC) alone, for 41 patients, and MMC in combination with local microwave-induced hyperthermia, for 42 patients. For the combined approach, a new system, Synergo101-1 (Medical Enterprises, Amsterdam, the Netherlands) was used. The effectiveness evaluation end points of the study were evaluation of recurrence-free survival and the estimated probability of recurrence. The safety evaluation end points included subjective and objective side effects and clinical complications. For the efficacy end point, Kaplan-Meier analysis was employed, with the log-rank test for significance. Minimum follow-up time was 24 months. RESULTS Of the 83 randomly assigned patients, 75 completed the study according to the protocol and had valid cystoscopy results. Survival analysis of the 75 assessable patients demonstrated a highly significant difference in the survival curves in favor of thermochemotherapy. Subjective intolerance and clinical complications were significantly higher but transient and moderate in the combined treatment group. CONCLUSION In our series, endovesical thermochemotherapy appears to be more effective than standard endovesical chemotherapy as an adjuvant treatment for superficial bladder tumors at 24-month follow-up, despite an increased but acceptable local toxicity.

Pelvic/Retroperitoneal Salvage Lymph Node Dissection for Patients Treated With Radical Prostatectomy With Biochemical Recurrence and Nodal Recurrence Detected by [11C]Choline Positron Emission Tomography/Computed Tomography

BACKGROUND The management of patients with clinical recurrence of prostate cancer after radical prostatectomy (RP) remains challenging. OBJECTIVE To determine whether the removal of positive lymph nodes at [11C]choline positron emission tomography/computed tomography (PET/CT) scan may have an impact on the prognosis of patients with biochemical recurrence (BCR) and nodal recurrence after RP. DESIGN, SETTING, AND PARTICIPANTS Prospective analysis of 72 patients affected by BCR after RP associated with a nodal pathologic [11C]choline PET/CT scan. INTERVENTION Patients underwent salvage lymph node dissection (LND). MEASUREMENTS Biochemical response (BR) to treatment was defined as prostate-specific antigen (PSA) <0.2 ng/ml at 40 d after salvage LND. Kaplan-Meier and Cox regression analyses addressed time to and predictors of clinical recurrence (CR) after salvage LND, respectively. RESULTS AND LIMITATIONS Overall, 56.9% of patients achieved BR. Mean and median follow-up after LND were 39.4 and 39.8 mo, respectively. The 5-yr BCR-free survival rate was 19%. Preoperative PSA <4 ng/ml (hazard ratio [HR]: 0.12; p = 0.005), time to BCR <24 mo (HR: 7.52; p = 0.005), and negative lymph nodes at previous RP (HR: 0.19; p=0.04) represented independent predictors of BR. Overall, 5-yr CR-free and cancer-specific survival were 34% and 75%, respectively. At multivariable analyses, only PSA >4 ng/ml (HR: 2.13; p=0.03) and the presence of retroperitoneal uptake at PET/CT scan (HR=2.92; p=0.004) represented independent preoperative predictors of CR. Similarly, the presence of pathologic nodes in the retroperitoneum (HR: 2.78; p=0.02), higher number of positive lymph nodes (HR: 1.04; p=0.006), and complete BR to salvage LND (HR: 0.31; p=0.002) represented postoperative independent predictors of CR. Main limitations consisted of the lack of a control group and the heterogeneity of patients included in the analyses. CONCLUSIONS Salvage LND is feasible in patients with BCR after RP and nodal pathologic uptake at [11C]choline PET/CT scan. Biochemical response after surgery can be achieved in a consistent proportion of patients. Although most patients invariably progressed to BCR after surgery at longer follow-up, 35% of patients showed the absence of CR at 5 yr.

A prospective study comparing paroxetine alone versus paroxetine plus sildenafil in patients with premature ejaculation.

PURPOSE We compared the efficacy of paroxetine alone and combined with sildenafil in patients complaining of premature ejaculation. MATERIALS AND METHODS Enrolled in this study were 80 consecutive potent men 19 to 47 years old (mean age 34) with premature ejaculation but without any obvious organic cause. Pretreatment evaluation included a history, self-administration of the International Index of Erectile Function (IIEF) questionnaire, physical examination and the Meares-Stamey test to exclude genital tract infection. The initial 40 patients received 10 mg. paroxetine daily for 21 days and then 20 mg. as needed, that is 3 to 4 hours before planned sexual activity, for 6 months (group 1). The other group of 40 men received 10 mg. paroxetine daily for 21 days and then 20 mg. as needed plus 50 mg. sildenafil as needed, that is 1 hour before planned sexual activity, for 6 months (group 2). Patients were followed 3 and 6 months after beginning therapy and were evaluated using several general assessment questions, IIEF and ejaculatory latency time. RESULTS Mean ejaculatory latency time +/- SE in group 1 was 0.33 +/- 0.04, 3.7 +/- 0.10 (p <0.01) and 4.2 +/- 0.03 (p <0.01) minutes at baseline, 3 and 6-month followup, while in group 2 it was 0.35 +/- 0.03, 4.5 +/- 0.07 (p <0.01) and 5.3 +/- 0.02 (p <0.001) minutes, respectively. When improvement in ejaculatory latency time was compared in the 2 groups, group 2 results proved to be significantly greater (p <0.05). Baseline, and 3 and 6-month mean intercourse satisfaction domain values of the IIEF were 9, 11 and 11 (p = 0.09, not significant), and 9, 11 and 14 (p <0.05) in groups 1 and 2, respectively. Group 2 patients reported significantly greater intercourse satisfaction than those in group 1 (p <0.05). At baseline, 3 and 6 months there was a mean of 0.9 +/- 0.1, 1.7 +/- 0.3 (not significant) and 2.5 +/- 0.3 (p <0.01) coitus episodes weekly in group 1, and 1 +/- 0.2, 2.3 +/- 0.3 (p <0.01) and 3.2 +/- 0.1 (p <0.001) in group 2, respectively. Group 2 patients reported a significantly higher number of coitus episodes weekly (p <0.05). Side effects in the 40 group 1 cases included anejaculation in 1 (2.5%), gastrointestinal upset and/or nausea in 5 (12.5%), headache in 4 (10%) and decreased libido in 2 (5%). Side effects in the 40 group 2 cases included anejaculation in 1 (2.5%), headache in 8 (20%), gastrointestinal upset and/or nausea in 6 (15%) and flushing in 6 (15%). Group 2 patients reported significantly more headaches (p <0.01) and flushing episodes (p <0.001) than those in group 1. After 6 months of treatment 33 men (82.5%) in group 1 and 36 (90%) in group 2 were willing to continue therapy (not significant). CONCLUSIONS Paroxetine combined with sildenafil appears to provide significantly better results in terms of ejaculatory latency time and intercourse satisfaction versus paroxetine alone in potent patients with premature ejaculation. However, combined treatment is associated with a mild increase in drug related side effects.

Long-term Outcomes of Salvage Lymph Node Dissection for Clinically Recurrent Prostate Cancer: Results of a Single-institution Series with a Minimum Follow-up of 5 Years

BACKGROUND Prostate cancer (PCa) patients with lymph node recurrence after radical prostatectomy (RP) are usually managed with androgen-deprivation therapy. Despite the absence of prospective randomized studies, salvage lymph node dissection (LND) has been proposed as an alternative treatment option. OBJECTIVE To examine long-term outcomes of salvage LND in patients with nodal recurrent PCa documented by 11C-choline positron emission tomography/computed tomography (PET/CT) scan. DESIGN, SETTING, AND PARTICIPANTS Overall, 59 patients affected by biochemical recurrence (BCR) with 11C-choline PET/CT scan with pathologic activity treated between 2002 and 2008 were included. INTERVENTION Pelvic and/or retroperitoneal salvage LND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES Biochemical response (BR) was defined as prostate-specific antigen (PSA) <0.2 ng/ml at 40 d after surgery. BCR for those who achieved BR was defined as a PSA >0.2 ng/ml. Clinical recurrence (CR) was defined as a positive PET/CT scan after salvage LND in the presence of a rising PSA. Kaplan-Meier curves assessed time to BCR, CR, and cancer-specific mortality (CSM). Cox regression analyses were fitted to assess predictors of CR. RESULTS AND LIMITATIONS Median follow-up after salvage LND was 81.1 mo. Overall, 35 patients (59.3%) achieved BR. The 8-yr BCR-free survival rate in patients with complete BR was 23%. Overall, the 8-yr CR- and CSM-free survival rates were 38% and 81%, respectively. In multivariable analyses evaluating preoperative variables, PSA at salvage LND represented the only predictor of CR (p=0.03). When postoperative variables were considered, BR and the presence of retroperitoneal lymph node metastases were significantly associated with the risk of CR (all p ≤ 0.04). Our study is limited by the lack of a control group. CONCLUSIONS Salvage LND may represent a therapeutic option for patients with BCR after RP and nodal pathologic uptake at 11C-choline PET/CT scan. Although most patients progressed to BCR after salvage LND, roughly 40% of them experienced CR-free survival. PATIENT SUMMARY Salvage lymph node dissection may represent a therapeutic option for selected patients with nodal recurrence after radical prostatectomy. Roughly 40% of men did not show any further clinical recurrence at long-term follow-up after surgery.

The Role of a Combined Regimen With Intravesical Chemotherapy and Hyperthermia in the Management of Non-muscle-invasive Bladder Cancer: A Systematic Review

CONTEXT Due to the suboptimal clinical outcomes of current therapies for non-muscle-invasive bladder cancer (NMIBC), the search for better therapeutic options continues. One option is chemohyperthermia (C-HT): microwave-induced hyperthermia (HT) with intravesical chemotherapy, typically mitomycin C (MMC). During the last 15 yr, the combined regimen has been tested in different clinical settings. OBJECTIVE To perform a systematic review to evaluate the efficacy of C-HT as a treatment for NMIBC. EVIDENCE ACQUISITION The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken. Relevant conference abstracts and urology journals were also searched manually. Two reviewers independently reviewed candidate studies for eligibility and abstracted data from studies that met inclusion criteria. The primary end point was time to recurrence. Secondary end points included time to progression, bladder preservation rate, and adverse event (AE) rate. EVIDENCE SYNTHESIS A total of 22 studies met inclusion criteria and underwent data extraction. When possible, data were combined using random effects meta-analytic techniques. Recurrence was seen 59% less after C-HT than after MMC alone. Due to short follow-up, no conclusions can be drawn about time to recurrence and progression. The overall bladder preservation rate after C-HT was 87.6%. This rate appeared higher than after MMC alone, but valid comparison studies were lacking. AEs were higher with C-HT than with MMC alone, but this difference was not statistically significant. CONCLUSIONS Published data suggest a 59% relative reduction in NMIBC recurrence when C-HT is compared with MMC alone. C-HT also appears to improve bladder preservation rate. However, due to a limited number of randomized trials and to heterogeneity in study design, definitive conclusions cannot be drawn. In the future, C-HT may become standard therapy for high-risk patients with recurrent tumors, for patients who are unsuitable for radical cystectomy, and in cases for which bacillus Calmette-Guérin treatment is contraindicated.

Prognostic Value of Lymph Node Dissection in Patients with Muscle-Invasive Transitional Cell Carcinoma of the Upper Urinary Tract

OBJECTIVES To analyze the prognostic role of lymphadenectomy (LND) in patients with muscle-invasive transitional cell carcinoma (TCC) of the upper urinary tract (UUT) managed with radical surgery. METHODS From 1986 to 2003, 132 consecutive patients with muscle-invasive TCC of the UUT underwent radical surgery. LND was performed in 95 cases. Patients were stratified according to the presence of LND and lymph node (LN) status. Univariable and multivariable Cox regression models determined the effect of age, pT, grade, nodal status (pN), number of LNs removed, year of surgery, and postoperative chemotherapy on disease-free survival (DFS) and cancer-specific survival (CSS) in the overall population and in patients who underwent LND. RESULTS The actuarial 5-yr CSS in pNx patients was significantly worse than in pN0 patients (48% vs. 73%, p=0.001) and comparable to pN+ outcome (48% vs. 39%, p=0.476). In the entire population, multivariable Cox regression analyses indicated that pT and pN status were independent predictors of DFS (p=0.04, hazard ratio [HR]=1.82 and p<0.01, HR=1.34, respectively) and CSS (p<0.01, HR=2.42 and p=0.04, HR=1.32, respectively). In patients who underwent LND, the number of LNs removed was an independent predictor of DFS (p=0.03, HR=0.928) and of CSS (p=0.007, HR=0.903). The extent of LND again resulted in an independent predictor either of DFS or CSS (p=0.04, HR=0.904 and p=0.01, HR=0.867, respectively) in the subgroup of pN0 patients. CONCLUSIONS LND emerged as a strong independent predictor of DFS and CSS in patients surgically managed for a muscle-invasive TCC of the UUT.

Significant upgrading affects a third of men diagnosed with prostate cancer: predictive nomogram and internal validation

To explore the rate of significant upgrading from biopsy to radical prostatectomy (RP) specimens in a contemporary cohort, and to develop a prognostic model capable of predicting the probability of significant upgrading, as previous reports indicate that up to 43% of men with low‐grade prostate cancer at biopsy will be diagnosed with high‐grade cancer at RP.

LONG-TERM OUTCOMES OF A RANDOMIZED CONTROLLED TRIAL COMPARING THERMOCHEMOTHERAPY WITH MITOMYCIN-C ALONE AS ADJUVANT TREATMENT FOR NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC)

1 Colombo R, Salonia A, Leib Z, PavoneMacaluso M, Engelstein D. Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). BJU Int 2010; 107 : 912–9 2 Halachmi S, Moskovitz B, Maffezzini M et al . Intravesical mitomycin C combined with hyperthermia for patients with T1G3 transitional cell carcinoma of the bladder. Urol Oncol 2009 [Epub ahead of print]. DOI: 10.1016/j.urolonc.2009.02.012 3 Smits G, Schaafsma E, Kiemeney L, Caris C, Debruyne F, Witjes JA: Microstaging of pT1 transitional cell carcinoma of the bladder: identification of subgroups with distinct risks of progression. Urology 1998; 52 : 1009–14

Neoadjuvant Combined Microwave Induced Local Hyperthermia and Topical Chemotherapy Versus Chemotherapy Alone for Superficial Bladder Cancer

PURPOSE We evaluated the effectiveness of local bladder hyperthermia and intravesical chemotherapy compared to intravesical chemotherapy alone in the treatment of superficial transitional cell carcinoma. MATERIALS AND METHODS A new system designed to deliver simultaneously local bladder hyperthermia and intravesical chemotherapy has been developed at our institute. The system consists of a computerized 915 MHz. microwave source that directly heats the bladder walls (within a temperature range of 42.5 to 45.5C) using a transurethral catheter. From February 1989 to December 1993, 52 patients 44 to 81 years old (mean age 64.3) with superficial stages Ta to T1, grades 1 to 3 transitional cell carcinoma of the bladder were selected for neoadjuvant intracavitary treatment. Tumors were left intact as marker lesions. Of the patients 29 were randomly assigned to receive combined neoadjuvant intravesical chemotherapy and local hyperthermia (group 1), while 23 received intravesical chemotherapy alone (group 2). The treatment protocol included multiple sessions performed on an outpatient basis. Mitomycin C (40 mg. in 50 cc distilled water) was used for intravesical chemotherapy in both groups. All patients underwent transurethral resection of residual tumors and of all suspicious areas 7 to 10 days after completion of treatment. Only a complete response was considered for statistical analysis. RESULTS A pathological complete response was documented in 19 cases (66%) in group 1 and 5 (22%) in group 2 (chi-square p< 0.01). CONCLUSIONS According to these preliminary data, microwave induced hyperthermia combined with local intravesical chemotherapy seems to be a feasible, safe and promising approach for neoadjuvant and minimally invasive treatment of superficial bladder cancer.

Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC): RCT COMPARING THERMOCHEMOTHERAPY WITH MITOMYCIN-C ALONE AS ADJUVANT TREATMENT FOR NMIBC

Study Type – Therapy (RCT) Level of Evidence 1b