Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC).

OBJECTIVE: • To present long-term efficacy data of intravesical thermochemotherapy vs chemotherapy alone with mitomycin-C (MMC) randomly administered to patients with non-muscle-invasive bladder cancer (NMIBC) as an adjuvant treatment after complete transurethral resection. PATIENTS AND METHODS: • In all, 83 patients with intermediate-/high-risk NMIBC, following complete transurethral resection, were randomly assigned to receive either intravesical thermochemotherapy by means of Synergo® (Medical Enterprises, Amsterdam, The Netherlands) or intravesical chemotherapy alone, for prophylaxis of tumour recurrence. • Two doses of MMC (20 mg dissolved in 50 mL distilled water administered throughout two consecutive sessions) was used as the chemotherapeutic agent in both arms. • In all, 75 patients completed the original study (35 of 42 in the treatment arm, 40 of 41 in the control arm), whose results at minimum 2-year follow-up have already been published. • Recently, the files of these patients have been updated for long-term outcome definition. Data on general health, follow-up examinations, tumour relapse or progression, and cause of death were collected and analysed. RESULTS: • Updated complete data collection was available for 65/75 (87%) of the original patients. • The median follow-up for tumour-free patients was 91 months. The 10-year disease-free survival rate for thermochemotherapy and chemotherapy alone were 53% and 15%, respectively (P < 0.001). • An intent-to-treat analysis performed to overcome the potential bias introduced by the asymmetrical discontinuation rate still showed a significant advantage of the active treatment over the control treatment. Bladder preservation rates for thermochemotherapy and chemotherapy alone were 86% and 79%, respectively. CONCLUSION: • This is the first analysis of long-term follow-up of patients treated with intravesical thermochemotherapy. The high rate (53%) of patients who were tumour-free 10 years after treatment completion, as well as the high rate (86%) of bladder preservation, confirms the efficacy of this adjuvant approach for NMIBC at long-term follow-up, even in patients with multiple tumours.

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.

Epidemiology and statistical methods in prediction of patient outcome.

Substantial gaps exist in the data of the assessment of risk and prognosis that limit our understanding of the complex mechanisms that contribute to the greatest cancer epidemic, prostate cancer, of our time. This report was prepared by an international multidisciplinary committee of the World Health Organization to address contemporary issues of epidemiology and statistical methods in prostate cancer, including a summary of current risk assessment methods and prognostic factors. Emphasis was placed on the relative merits of each of the statistical methods available. We concluded that: 1. An international committee should be created to guide the assessment and validation of molecular biomarkers. The goal is to achieve more precise identification of those who would benefit from treatment. 2. Prostate cancer is a predictable disease despite its biologic heterogeneity. However, the accuracy of predicting it must be improved. We expect that more precise statistical methods will supplant the current staging system. The simplicity and intuitive ease of using the current staging system must be balanced against the serious compromise in accuracy for the individual patient. 3. The most useful new statistical approaches will integrate molecular biomarkers with existing prognostic factors to predict conditional life expectancy (i.e. the expected remaining years of a patient's life) and take into account all-cause mortality.

Correlation between GP-170 expression, prognosis, and chemoresistance of superficial bladder carcinoma.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. A joint proposal of the European Society of Uropathology and the Uropathology Working Group.

Pathologists play a pivotal role in the diagnosis and in the report of the pathological features related to prognosis. To meet these endpoints, the following issues must be addressed: adequate information about the patient history, proper handling of the specimens, identification of the reliable histopathological techniques necessary to reach the more detailed diagnostic information and evaluation of the prognostic variables, and standardized pathological reporting. In this review we discuss a proposal for standardization of sampling and reporting of the urothelial tissues achieved within uropathology. The urologists have a great role in assisting pathologists in the proper examination by providing them with clinical information.

Does P-glycoprotein-170 expression predict for chemoresistance in transitional cell carcinoma of the bladder?

INTRODUCTION: The glycoprotein P-170, causing drug efflux from the cells, may represent at least one cause of resistance to most drugs used in intravesical chemotherapy of superficial bladder cancer. MATERIALS AND METHODS: GP-170 was retrospectively assessed in 60 patients affected by superficial transitional cell tumours of the bladder. It was assessed by immunohistochemistry in a semiquantitative way by the intensity of staining and by the percentage of positive cells. Correlation of GP-170 expression with G-grade, T-category, multiplicity, recurrence rate and treatment was investigated. In 44 patients recurrence was analysed in relation to GP-170 basal expression and to its variations. The monoclonal antibody JSB1 (DBA) at 1:20 dilution was employed for the GP-170 assay. RESULTS: GP-170 expression increases with grade but was lower in multiple tumours. No difference between Ta and T1 categories was detected. GP-170 immunohistochemistry from different portions of the same tumour showed a very marked variability in 35.7% of patients. Seven patients (11.6%) were totally negative for GP-170. No statistically significant correlation was found between recurrence, progression and GP-170 basal expression. Similarly no correlation emerged between grade and stage variations at recurrence and modifications in GP-170 expression. One third of the tumours recurring after chemotherapy were negative for GP-170 in spite of an increase in recurrence rate and other risk factors. CONCLUSION: At the present stage of our experience, we have been unable to show that GP-170 is a useful marker for monitoring chemoresistance to intravesical chemotherapy in superficial bladder cancer. Furthermore, GP-170 determination has shown several technical difficulties.

Words of wisdom. Re: Does oral antiandrogen use before leuteinizing hormone-releasing therapy in patients with metastatic prostate cancer prevent clinical consequences of a testosterone flare? Oh WK, Landrum MB, Lamont EB, et al. Urology 2010;75:642-7.

Oh et al report their experience with 1566 metastatic prostate cancer patients treated with luteinising hormone-releasing hormone (LHRH) agonists in the area of Boston, Massachusetts, USA. Of these patients, 79.5% were given antiandrogens (bicalutamide, flutamide, or nilutamide) before the first LHRH agonist dose. The remaining patients (20.5%) did not receive antiandrogens. In all patients, complications appearing within 30 d and attributable to a flare phenomenon (fractures, spinal cord compression, bladder outlet obstruction, exacerbation of pain) were assessed retrospectively. Such complications were extremely rare (<1%) in both groups. There was no difference whether or not antiandrogens were administered. The timing of antiandrogen prescription(0-6 vs > or =7 d before starting the LHRH analogues) made no difference.The authors concluded that no evidence supports a generalised use of antiandrogens in addition to the LHRH agonists. The risks of antiandrogen therapy (hepatic,gastrointestinal, ocular, and pulmonary complications)may counterbalance the benefits of the combined therapy,which is much more expensive.

The pathology of bladder cancer: An update on selected issues.

OBJECTIVE: To achieve a closer relationship between urologists and pathologists and to use a common language and identical objectives in the pathology of bladder cancer. METHODS AND RESULTS: Special emphasis was given to an analysis of the new World Health Organization (WHO) grading system, to the interpretation of the last Tumour-Nodes-Metastasis staging rules, and to identifying new markers of prognostic significance in clinical practice. A consensus was achieved on the main points. CONCLUSIONS: The 2004 WHO grading system must become acceptable to clinicians, perhaps by a minimal modification of the present terminology. Simple transurethral resection-biopsy should be expressed in terms of clinical rather than pathological staging. Although there are substantial improvements, no new markers can be recommended for routine use in histopathology at present.

Gemcitabine in intravesical treatment of Ta-T1 transitional cell carcinoma of bladder: Phase I-II study on marker lesions.

OBJECTIVES: To study the ablative activity of intravesical gemcitabine against superficial transitional cell carcinoma of the bladder at different doses and concentrations. METHODS: A total of 27 patients were treated with intravesical gemcitabine after transurethral resection during which one to three papillary marker lesions were left unresected. Starting 14 days after transurethral resection, six instillations of gemcitabine were given at weekly intervals. Gemcitabine, diluted in 50 mL of saline solution and maintained for 2 hours, was given at the dose of 500 mg, 1000 mg, and 2000 mg in groups of 9 patients each. A complete response (CR) was defined as negative cytology, cystoscopy, and biopsy findings. Patients achieving a CR received monthly maintenance for up to 1 year and underwent cytology and cystoscopy at 3-month intervals. RESULTS: Of the 27 patients, 1 was lost to follow-up, and of the remaining 26 patients, 6 (23%) achieved a CR. A CR was achieved in 1 patient (12.5%), 2 patients (22.2%), and 3 patients (33.3%) at a dose of 500, 1000, and 2000 mg, respectively. A partial response was obtained in 2 additional patients (22%) at a dose of 500 and 1000 mg. Bladder Tis was diagnosed in 2 patients with a CR at 3 and 8 months after treatment. The remaining 4 patients were disease free at a follow-up of up to 22 months. Systemic and local tolerability was excellent, and no treatment interruption was required. CONCLUSIONS: Our experience has shown the good tolerability and potential efficacy of intravesical gemcitabine against recurrent transitional cell carcinoma of the bladder. Gemcitabine might be proposed, if our results are confirmed by larger studies, as a second-line therapy in patients who cannot tolerate more aggressive intravesical therapy.

TUR and adjuvant intravesical chemotherapy in T1G3 bladder tumors: recurrence, progression and survival in 137 selected patients followed up to 20 years.

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<0.001) after conservative treatment was the main prognostic factor for survival. CONCLUSION: A conservative approach is an appropriate therapeutic option for the initial management of selected T1G3 bladder tumors.

Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis.

OBJECTIVE: Pathologists play a pivotal role in the diagnosis and in the report of the pathological features related to prognosis. METHODS: To meet these endpoints, the following issues must be accomplished: adequate information about the patient history, proper handling of the specimens, identification of the reliable histopathological techniques necessary to reach the more detailed diagnostic information and evaluate the prognostic variables, and a standardized pathological report. RESULTS: Recent efforts to standardize the histopathological evaluation have generated significant confusion among the urological and pathological communities as well. No consensus has been achieved about the optimal pathological grading of urothelial tumors, to date. CONCLUSION: A proposal for standardization of sampling and reporting of the urothelial tissues achieved within Uropathology follows. The urologists have a great role in assisting pathologists in the proper examination by providing them with clinical information.

Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final analysis of the "European Organization for Research and Treatment of Cancer" (EORTC) Protocol 30892.

OBJECTIVES: This trial was designed to compare the efficacy of Flutamide (FLU) versus Cyproterone acetate (CPA) in men with metastatic prostate cancer and favourable prognostic factors. The primary endpoint of the trial was overall survival, disease specific survival, time to progression and side effects were secondary endpoints. The results pertaining to sexual function were already reported [Br J Cancer 82(2) (2000) 283]. MATERIAL AND METHODS: The trial was designed to detect a 50% improvement in median overall survival with 80% power. At the time of the present report, the trial provides 88% power to detect the planned difference of 50% with a 2-sided Logrank test and 80% power to detect a difference of 43% in median survival. RESULTS: 310 patients were randomized to treatment by FLU (250 mg t.i.d. p.o.) or CPA (100 mg t.i.d. p.o.). Of the 310 patients, 12 (3.9%) were ineligible. The baseline characteristics of the two groups were similar except for age which was significantly younger in the CPA group and for the presence of soft tissue metastases which were absent in the FLU group and present in 6 patients in the CPA group. The median follow-up was 8.6 years, 245 patients died, 158 (64.5%) of prostate cancer. There was no significant difference between the treatment arms with respect to overall survival, specific survival nor time to progression. Side effect profiles were studied and found to be more favourable for CPA overall and in particular with respect to gynecomastia, diarrhea and nausea. CONCLUSIONS: The trial shows no significant differences in efficacy between Flutamide and CPA monotherapy. The number of patients who died of prostate cancer up to this time is insufficient for a definitive analysis of specific survival. Erectile function and sexual activity are not preserved with FLU but decay slowly with both antiandrogens, toxicity is more pronounced with FLU.

Management of symptomatic benign prostatic hyperplasia in southern Italy: a retrospective analysis of the Sicilian-Calabrian Society of Urology (SSCU) of 32,000 patients.

INTRODUCTION: The availability of new pharmacological and surgical options is responsible for important changes in the management of symptomatic benign prostate hyperplasia (BPH). The Sicilian-Calabrian Society of Urology performed a retrospective survey to assess the management of BPH in southern Italy in 1997 and 1998. PATIENTS AND METHODS: A 3-page questionnaire was sent to the 36 urological units of these two regions. The real number of patients treated was required. The numbers were checked with data obtained from the Health Regional Offices. RESULTS: Twenty-six urological units (72.3%) replied. Almost all patients underwent urinalysis, determination of serum prostate-specific antigen and creatinine levels, and renal and postvoid vesical echography. Uroflowmetry was performed in 69% and transrectal ultrasound in 56% of the patients. International Prostate Symptom Score or other symptom scores were used in 36% of the cases. Out of 31,558 patients with symptomatic BPH, 5,636 were surgically treated. Admission was due to acute urinary retention in 1,324 cases (23.5%). Transurethral resection of the prostate was the commonest procedure, accounting for 59.5% of the interventions. Open prostatectomy was performed in 1,804 patients (32%). Minimally invasive therapies accounted for less than 9% of the treatments. CONCLUSIONS: The present survey provides a picture of the current surgical practice in BPH in southern Italy in the late 1990s. Symptom scores are not routinely adopted. The low rate of transurethral prostate resections is in keeping with the worldwide decline. On the contrary, a high rate of open prostatectomies has been detected.

Open prostatectomy for benign prostatic enlargement in southern Europe in the late 1990s: a contemporary series of 1800 interventions.

OBJECTIVES: Contemporary series of open prostatectomies from Western countries are rare. Frequently, the analysis of the outcome of open prostatectomy refers to old experiences or to series from developing countries. Any comparison with transurethral resection of the prostate can be invalidated by complications of open surgery because of the lack of an adequate healthcare system and technology. METHODS: The Sicilian-Calabrian Society of Urology performed a retrospective study to assess the surgical management of benign prostatic hyperplasia in Sicily and Calabria in 1997 and 1998. A three-page questionnaire was sent to the 36 urologic units of these two Italian regions with more than 7.5 million inhabitants. RESULTS: Twenty-six units (72.3%) replied. Of 31,558 patients treated for symptomatic benign prostatic hyperplasia, 5636 underwent surgery. Open prostatectomy (n = 1804) accounted for 32% of all surgical treatment. The median prostate volume was 75 cm(3) and the median serum prostate-specific antigen level was 3.7 ng/mL. The postoperative median hospitalization time was 7 days. Concomitant low urinary tract disease was present in 25% of the patients. Severe bleeding occurred in 11.6% of open prostatectomies. Blood transfusions were given in 8.2% of cases. Sepsis was reported in 8.6% of the patients. Reinterventions, within 2 years, mainly due to bladder neck stenosis, were reported in 3.6% of cases. CONCLUSIONS: The results of the present survey provide a current picture of open prostatectomy. This procedure, even if performed nowadays and in Western countries, shows the same significant rate of early and late complications reported in the past or in less-developed countries.