Focal laser ablation as clinical treatment of prostate cancer: report from a Delphi consensus project.

PURPOSE: To define the role of focal laser ablation (FLA) as clinical treatment of prostate cancer (PCa) using the Delphi consensus method. METHODS: A panel of international experts in the field of focal therapy (FT) in PCa conducted a collaborative consensus project using the Delphi method. Experts were invited to online questionnaires focusing on patient selection and treatment of PCa with FLA during four subsequent rounds. After each round, outcomes were displayed, and questionnaires were modified based on the comments provided by panelists. Results were finalized and discussed during face-to-face meetings. RESULTS: Thirty-seven experts agreed to participate, and consensus was achieved on 39/43 topics. Clinically significant PCa (csPCa) was defined as any volume Grade Group 2 [Gleason score (GS) 3+4]. Focal therapy was specified as treatment of all csPCa and can be considered primary treatment as an alternative to radical treatment in carefully selected patients. In patients with intermediate-risk PCa (GS 3+4) as well as patients with MRI-visible and biopsy-confirmed local recurrence, FLA is optimal for targeted ablation of a specific magnetic resonance imaging (MRI)-visible focus. However, FLA should not be applied to candidates for active surveillance and close follow-up is required. Suitability for FLA is based on tumor volume, location to vital structures, GS, MRI-visibility, and biopsy confirmation. CONCLUSION: Focal laser ablation is a promising technique for treatment of clinically localized PCa and should ideally be performed within approved clinical trials. So far, only few studies have reported on FLA and further validation with longer follow-up is mandatory before widespread clinical implementation is justified.

Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project.

PURPOSE: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa). METHODS: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated. RESULTS: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text. CONCLUSION: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice.

Follow-up modalities in focal therapy for prostate cancer: results from a Delphi consensus project.

INTRODUCTION: Focal therapy can offer the middle ground for treatment between active surveillance and radical therapy in patients with low- and intermediate-risk prostate cancer. Factors that prohibit focal therapy from being standard of care are numerous. Several consensus projects have been conducted to position the utilization of imaging and trial design in focal therapy. However, the literature is still scarce on patient follow-up after focal therapy. For these reasons, an international multidisciplinary consensus project was established in order to reach consensus about a uniform follow-up protocol after focal therapy. OBJECTIVE: To standardize patient follow-up after focal therapy. MATERIALS AND METHODS: A literature study was performed, and a questionnaire was constructed. The questionnaire was sent out to 76 participants (70 % urologists, 28 % radiologists and 2 % biomedical engineers) in three consecutive rounds according to the Delphi method. In each round, the panelists were presented with the results of the previous round. Participants each had the opportunity to adapt, delete or add questions. The topics discussed pertaining to follow-up after focal therapy were as follows: (1) general,(2) biopsies, (3) PSA, (4) digital rectal examination (DRE), (5) imaging, (6) quality of life (QoL) and (7) registration and pooling of data. The project was concluded with a face-to-face meeting in which final conclusions were formulated. RESULTS: The follow-up after focal therapy should be a minimum of 5 years. The following modalities should be included in assessing post-treatment outcomes: multiparametric MRI (mpMRI), biopsies, assessment of erectile function, QoL, urinary symptoms and incontinence. A systematic 12-core TRUS biopsy combined with 4-6 targeted biopsy cores of the treated area and any suspicious lesion(s) should be performed after 1 year, and thereafter only when there is suspicion on imaging. The ideal way to perform targeted biopsies is to use TRUS-MRI fusion technology. PSA should be performed for research purposes, in the first year, every 3 months, and after the first year, every 6 months. mpMRI is the optimal imaging modality for follow-up after focal therapy. On a 1.5T scanner, an endorectal coil is strongly advised by the panel, whereas on a 3T machine, it is optional, however, it will improve image quality. The following sequences should be included: T2WI, DWI including high b values of >1,000 and ADC maps of DWI, DCE and T1WI. Imaging should be performed at 6 months and at 1 year following treatment; after the first year post-treatment, it should be performed every year until 5 years following treatment. All data should ideally be pooled in a common global database. CONCLUSION: Focal therapy is a relatively new form of treatment for prostate cancer. In order to include focal therapy as a standard of care treatment, consistent follow-up is necessary. By implementing the results of this consensus study, focal therapy users will be able to provide important and standardized outcome data.

The clinical use of statistical permutation test methodology: a tool for identifying predictive variables of outcome.

OBJECTIVES: To identify the predictive variables affecting the outcome after radical surgery for bladder cancer by a newer statistical methodology, i.e. nonparametric combination (NPC). METHODS: A multicenter study enrolled 1,312 patients who had undergone radical cystectomy for bladder cancer in 11 Italian oncological centers from January 1982 to December 2002. A statistical analysis of their medical history and diagnostic, pathological and postoperative variables was performed using a NPC test. The patients were included in a comprehensive database with medical history and clinical and pathological data. Five-year survival was used as the dependent variable, and p values were corrected for multiplicity using a closed testing procedure. The newer nonparametric approach was used to evaluate the prognostic importance of the variables. All of the analyses were performed using routines developed in MATLAB© and the significance level was set at α = 0.05. RESULTS: A significant prognostic predictive value (p < 0.01) for tumor clinical staging, hydronephrosis, tumor pathological staging, grading, presence of concomitant carcinoma in situ, regional lymph node involvement, corpora cavernosa invasion, microvascular invasion, lymphatic invasion and prostatic stroma involvement was found. CONCLUSIONS: The NPC test could handle any type of variable (categorical and quantitative) and take into account the multivariate relation among variables. This newer methodology offers a significant contribution in biomedical studies with several endpoints and is recommended in presence of non-normal data and missing values, as well as solving high-dimensional data and problems relating to small sample sizes.

Management of high-risk non-muscle invasive bladder cancer.

Risk stratification is of paramount importance for the future treatment and follow-up of patients with transitional cell carcinoma (TCC) of the bladder. Transurethral resection (TUR) is the gold standard for initial diagnosis and treatment of non muscle invasive bladder cancer (NMIBC). Muscle must be present in the pathological specimen in order to correctly stage the tumor. When muscle is not present, the tumor has to be staged as Tx. A second TUR done after two-six weeks of the first resection reduces the rate of tumor left behind and improves staging. Re-TUR in these patients should be considered a must. Since BCG is toxic, an attempt to reduce toxicity was made by reducing the dose. CUETO group showed that 1/3 dose BCG was as effective as full dose in intermediate risk patients but not in high risk. Another study that evaluated the efficacy of low dose BCG is the trial 30962 from EORTC. The results showed a difference of 10% in the five-years recurrence free survival only when 1/3 dose BCG for one year (54.5%) was compared to Full dose BCG for three years (64.2%) suggesting that 1/3 dose or one year full dose are suboptimal treatments. Immediate radical cystectomy should be considered for high grade, multiple T1 tumors, T1 tumors located at a site difficult to resect, residual T1 tumors after resection or high grade tumors with CIS and lymphovascular invasion. Cystoscopy and cytology must be performed at three months. In the case of negative findings, following cystoscopy and cytology assessments have to be repeated every three months for three years, and every six months thereafter until five years, and then annually. For the group of patients with initial BCG induction therapy failure that are unfit or refuse radical cystectomy or have a low or intermediate grade disease an additional course of l BCG is a choice. For patients who failed before completion of maintenance BCG, radical cystectomy has to be considered in presence of a high grade T1 or CIS. BCG maintenance (full dose three years) after Re-TUR is the standard therapy in high-risk TCC of the bladder. Dose reduction to 1/3 dose or one year full dose are suboptimal treatments. Immediate radical cystectomy is indicated in young patients with high-grade T1 tumors who have at least one additional factor associated with a poor prognosis such as: multifocality, associated CIS, prostatic involvement, tumor located at a site difficult to resect, limphovascular invasion. Radical cystectomy is also indicated in patients who recur after three months of therapy as T1 high grade. Device assisted chemotherapy (EMDA, Synergo with MMC) may have a role in BCG failure or BCG resistant patients who cannot receive or refuse cystectomy. Postponing radical cystectomy until progression to muscle invasive disease may have a negative impact on survival.

Focal therapy in prostate cancer-report from a consensus panel.

PURPOSE: To establish a consensus in relation to case selection, conduct of therapy, and outcomes that are associated with focal therapy for men with localized prostate cancer. MATERIAL AND METHODS: Urologic surgeons, radiation oncologists, radiologists, and histopathologists from North America and Europe participated in a consensus workshop on focal therapy for prostate cancer. The consensus process was face to face within a structured meeting, in which pertinent clinical issues were raised, discussed, and agreement sought. Where no agreement was possible, this was acknowledged, and the nature of the disagreement noted. RESULTS: Candidates for focal treatment should have unilateral low- to intermediate-risk disease with clinical stage

A comparison of the efficacy and tolerability of tamsulosin and finasteride in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

In this multicentre, double-blind study, patients with LUTS/BPH were randomised to 26 weeks with finasteride 5 mg once daily (n=204) or tamsulosin 0.4 mg once daily (n=199). Double-blind treatment was continued for another 26 weeks (total treatment duration: 1 y). The primary efficacy parameter was the difference in mean change in total Symptom Problem Index (SPI) from baseline to end point at week-26 in the intention-to-treat (ITT) and per protocol (PP) populations. Tamsulosin induced a greater improvement in total SPI (-5.2 points or -37%) compared to finasteride (-4.5 points or -31%) at week-26 (P=0.055 in ITT and P=0.032 in PP). Tamsulosin improved urinary symptoms (particularly the more bothersome storage symptoms) and flow more quickly than finasteride. The difference was statistically significant for the SPI from week-1 (reduction, respectively, -2.5 vs -1.8 points, P=0.043) to week-18 and for Qmax from week-1 (increase, respectively, 2.3 vs 0.7 ml/s, P=0.0007) to week-12. Both treatments were well tolerated with a comparable incidence of adverse events, including urinary retention.

Frequency of positive biopsies after visual disappearance of superficial bladder cancer marker lesions.

INTRODUCTION AND OBJECTIVES: In phase II trials in superficial bladder cancer, marker lesions have been used to test the ablative activity of intravesical chemo- or immunotherapy. These studies provide important knowledge about drug activity and toxicity without exposing hundreds of patients in phase III trials to drugs which ultimately may not be successful in preventing tumour recurrence or progression. After treatment a deep biopsy was necessary at the site of the marker lesion even in the absence of any visual tumour. The question is if this biopsy, in the absence of any visual tumour, should be done. MATERIAL AND METHODS: The ablative effect of MMC, epirubicin, and quarter dose BCG instillations was evaluated in three different studies on a papillary marker lesion. Patients with multiple, primary or recurrent superficial bladder tumours were included. All visible Ta-T1 lesions were resected except for one marker lesion not exceeding 1 cm. TIS was excluded. In the last study, patients with T1 G3 tumours or multiple tumours >10 were also excluded. If the marker lesion disappeared completely, a deep biopsy was performed at the scar in order to prove histological disappearance of the tumour. RESULTS: 185 patients were evaluated. No visual tumours were seen in 110 patients and a TUR was performed in 101 of them. It revealed only 3 Ta lesions. In the 9 others no biopsy was performed but follow-up cystoscopy revealed no lesions. CONCLUSIONS: In the absence of any visual tumors, TUR and deep biopsy at the site of the scar of the marker lesion only rarely revealed (3 out of 110) the histological presence of a tumour. Therefore, this biopsy can be omitted in new marker lesion protocols in patient with Ta-T1, G1 G2 papillary superficial bladder tumours at intermediate risk for recurrence and low risk for progression.

Intravesical instillation of epirubicin, bacillus Calmette-Guerin and bacillus Calmette-Guerin plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the bladder: a European Organization for Research and Treatment of Cancer genito-urinary group randomized phase III trial.

PURPOSE: After transurethral resection, we compared the efficacy and side effects of weekly intravesical instillations of epirubicin, bacillus Calmette-Guerin (BCG), and BCG plus isoniazid during a 6-week interval followed by 3 weekly maintenance instillations at months 3, 6, 12, 18, 24, 30 and 36 in patients with intermediate and high risk Ta, T1 bladder cancer. MATERIALS AND METHODS: A total of 957 patients were randomized at 44 institutions in a phase III multicenter trial. RESULTS: The time to first recurrence was significantly longer in patients treated with BCG and BCG plus isoniazid compared to epirubicin (p = 0.0001) but there was no difference between the 2 BCG regimens (p = 0.27). Progression to muscle invasive cancer was rare (5%) and did not differ significantly among the 3 arms (p = 0.12). Drug induced cystitis was observed in 31% of the patients treated with epirubicin, 42% BCG and 45% BCG plus isoniazid. Systemic side effects, such as fever and malaise, were not observed in patients treated with epirubicin, but were noted in 31% BCG and 36% BCG plus isoniazid. CONCLUSIONS: Intravesical BCG with or without isoniazid provokes more side effects than epirubicin. Prophylactic isoniazid does not reduce the side effects of BCG, while BCG with or without isoniazid prolongs the time to first recurrence compared to epirubicin. Further followup is required before long-term conclusions can be made for progression-to-muscle invasive disease and survival.

Quality control of radical prostatectomy: a feasibility study.

The aim of this study was to assess whether the quality of the surgical act could be an important prognostic factor for patients undergoing radical prostatectomy. This study also aims to investigate whether the surgical quality can be assessed by any means. Questionnaires were collected from 23 different institutes including 232 radical prostatectomies (RPr) performed for T1T2 prostate cancer. Blood loss, duration of surgery, margin status, postoperative prostate specific antigen (PSA) and urinary incontinence were analysed and correlated with the yearly number of RPr performed. The mean values obtained for each parameter were very different in the various centres. The outcome in terms of tumour control and incontinence could not be related to a higher or lower number of RPr performed. Quality control of RPr is feasible on the basis of an analysis of a few parameters, such as surgical margins, postoperative PSA and incontinence, that might recognise urologists that perform better or poorer than a proposed average.

Thermo-chemotherapy and electromotive drug administration of mitomycin C in superficial bladder cancer eradication. a pilot study on marker lesion.

OBJECTIVE: To assess the feasibility and safety of two novel methods for intravesical chemotherapy administration in patients suffering from superficial bladder carcinomas. To draw preliminary considerations concerning the ablative effect on marker lesion using novel approaches compared to standard intravesical chemotherapy. METHODS: Eighty patients suffering from single, recurrent, low-stage, low-grade superficial bladder tumor entered a prospective nonrandomized study. Thirty-six of them were treated by means of mitomycin C instillation as a standard procedure. In 29 patients mitomycin C solution was administered in combination with local microwave-induced hyperthermia and in 15 patients the mitomycin C solution was administered according to the electromotive drug procedure. The treatment was scheduled as a short term neo-adjuvant regimen prior to transurethral resection. Feasibility and safety of the different procedures were evaluated on an outpatients basis. The local toxicity induced by different approaches was defined and compared using a subjective questionnaire. RESULTS: Both intravesical chemotherapy administered in combination with hyperthermia and according to the electromotive drug technique appeared to be feasible and safe. Local toxicity induced by thermo-chemotherapy was more severe than that registered for electromotive drug technique and standard intravesical chemotherapy. Local toxicity was always short and self healing without early or delayed major complications. A higher complete response rate on marker lesion was observed after thermo-chemotherapy compared to other administration methods. CONCLUSION: The intravesical administration of mitomycin C can be safely performed in the form of both thermo-chemotherapy and electromotive drug approach with an increased ablative success rate on small superficial tumor involving only minimal local side effects.

The ablative effect of quarter dose bacillus Calmette-Guerin on a papillary marker lesion of the bladder.

PURPOSE: Low dose bacillus Calmette-Guerin (BCG) for stage TaT1 transitional cell carcinoma of the bladder has been given in various studies with the aim of decreasing side effects while maintaining the same efficacy as full dose bacillus Calmette-Guerin. However, its application in clinical practice remains controversial. We examined the ablative activity and incidence of side effects of intravesical quarter dose BCG given for a papillary marker lesion of the bladder. MATERIALS AND METHODS: Included in our study were 44 patients with primary or recurrent, multiple but no more than 10 lesions of stage pTaT1, grades 1 to 2 transitional cell carcinoma of the bladder. Intravesical treatment begun 14 days after the complete transurethral resection of all visible tumors except 1 marker lesion no larger than 1 cm. consisted of instillations of 30 mg. Connaught strain BCG diluted in 50 ml. saline once weekly for 6 consecutive weeks. Two weeks after the last instillation any residual tumor was completely resected. In cases of complete disappearance of the marker lesion deep biopsy of the tumor area was done. Urine cytology was also performed. RESULTS: There was a complete response in 27 of the 44 patients (61%), no response in 12 (27%) and progression to carcinoma in situ in 1 (2%), while the response was not evaluable in 4. Local side effects included dysuria in 54% of cases and macroscopic hematuria in 39%. Neither BCG induced infection nor BCG sepsis was observed. CONCLUSIONS: Quarter dose BCG has a clear ablative effect on superficial bladder cancer with a 61% response rate. Phase III trials are now required to compare its efficacy and toxicity to those of full dose BCG.

Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group.

PURPOSE: Time to progression (TTP), overall survival, and quality of life (QL) were compared in patients with hormone-resistant prostate cancer (HRPC) treated with prednisone (5 mg orally, four times a day) or flutamide (250 mg orally, three times a day). PATIENTS AND METHODS: Symptomatic patients were randomized to receive either prednisone (101 patients) or flutamide (100 patients). Subjective response was assessed based on performance status, the use of analgesics, and the need to apply alternative palliative treatment. Prostate-specific antigen (PSA)-based biochemical response (>or= 50% reduction of baseline PSA) was recorded. At baseline and at 6-week intervals during follow-up, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30. RESULTS: There was no difference between the groups in median TTP (prednisone, 3.4 months; flutamide, 2.3 months) or overall survival (prednisone, 10.6 months; flutamide, 11.2 months). In the prednisone group, 56% of the patients experienced a subjective response, compared with 45% in the flutamide group (P: = .18). The median response duration was 4.8 months for prednisone and 4.2 months for flutamide. A biochemical response was observed in 21% and 23% of the prednisone and flutamide groups, respectively. Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone. The QL assessment parameters favored the use of prednisone with statistically significant differences in pain, fatigue, role functioning, appetite loss, gastrointestinal distress, and overall QL. CONCLUSION: In symptomatic HRPC, treatment with prednisone or flutamide leads to similar rates of TTP and overall survival and no difference in subjective or biochemical response. The QL results favor the use of low-cost prednisone in patients with HRPC.

Nerve and seminal sparing radical cystectomy with orthotopic urinary diversion for select patients with superficial bladder cancer: an innovative surgical approach.

PURPOSE: Radical cystectomy is advocated for high risk patients with superficial bladder cancer. To preserve complete urinary continence, normal sexual function and fertility in young patients, we developed an innovative technique based on nerve and seminal sparing radical cystectomy. MATERIALS AND METHODS: Radical cystectomy was recommended for 8 patients with superficial bladder cancer that was not conservatively manageable. Average patient age was 44 years (range 36 to 48), and all patients were extremely anxious to maintain potency and fertility. The surgical procedure consisted of transurethral resection of the prostate, pelvic iliac lymph node dissection and extraperitoneal radical cystectomy performed while preserving the vas deferens seminal vesicles and neurovascular bundles. Urinary diversion was accomplished with a W-shaped ileal reservoir anastomosed to the prostatic capsule. RESULTS: Patients were generally discharged from the hospital 15 days after surgery, and postoperative morbidity was limited. Daytime and nighttime continence was immediate and complete after catheter removal. Normal erectile function was clinically documented in all patients while fertility potential with semen retrieval via urine was recorded in 7. The quality of life, as reported by the patients, was highly satisfactory at 18-month followup. CONCLUSIONS: The surgical approach we describe should be considered in young men with clinical, superficial bladder tumors refractory to conservative treatment who wish to maintain potency and fertility, and to guarantee as good a quality of life as possible. To ensure oncological success scrupulous patient selection is a primary step of this procedure.

Treatment of superficial bladder tumors: achievements and needs. The EORTC Genitourinary Group.

OBJECTIVE: The therapeutic objectives in the initial treatment of superficial tumors are to remove completely the tumor, to assess the need for further therapy and to plan the follow-up. METHODS/RESULTS: The EORTC Genitourinary Group assessed the percentage of patients with recurrence at 3 months (3RR) after complete resection of all visible lesions taking into account the institution, the number of tumors at presentation and the year of treatment. The 3RR was considered for 18 institutions. For single tumors, the 3RR varied from 0 to 36% and for multiple tumors from 7 to 75%. The 3RR by number of tumors was 8.7% for single tumors, 21% for 2-5 tumors and 32.2% for >5 tumors. The 3RR by year of entry for single tumors ranged from 21.0 to 43.8% during 1975-1978, from 6.3 to 12.7% during 1984-1986 and from 3 to 5.3% during 1987-1989. For multiple tumors it ranged from 50.0 to 61.5% during 1975-1978, from 20.2 to 27.3% during 1979-1983 and from 14.4 to 24.6% during 1984- 1986. The use of more refined instruments probably led to the decreasing percentage of the 3RR in more recent years, the large variation between institutions remains unexplained. The bladder's unique location renders its mucosa accessible to instillation of chemotherapeutic and immunotherapeutic agents. Cytostatics can be instilled into the bladder hours after surgery without severe complications. A single early instillation within 6 h after transurethral resection (TUR) in patients with a solitary bladder tumor category T(a)/T(1)G(1) to G(3) could reduce the recurrence rate per year by nearly 50%. The superiority of any of the commonly used intravesical drugs has never been demonstrated; the time to initiate therapy is important for treatment outcome. Optimal results can be achieved by initiating treatment early (within 24 h after TUR) and for a duration of 6 months, and maintenance (>6 months) for patients with a delayed first instillation (>7 days after TUR). Bacillus Calmette-Guérin (BCG) immunotherapy has been confirmed to be highly effective in the reduction of tumor recurrence, the treatment of residual papillary transitional cell carcinoma and the treatment of carcinoma in situ (CIS). The response rate in the treatment of the papillary disease averages 55%, and for CIS 73%. In the prevention of tumor recurrence the relative benefit of BCG is 45%. A direct prospective randomized comparison of BCG with intravesical chemotherapy has found it to be significantly superior to thiotepa, to doxorubicin and to mitomycin C when only patients with intermediate and high risk for recurrence were treated. In studies including patients with low recurrence risk, no advantage for BCG was found. Clinical trials showed no superiority of BCG immunotherapy to chemotherapy in preventing progression to > or =T(2). CONCLUSIONS: Investigation of the concept of chemoimmunotherapy up to now lacked evidence of advantages for this approach. Preventive regulatory measures directed to decrease tobacco smoking and some occupational exposures to aromatic amines may contribute to the reduction of bladder cancer. Bladder cancer is a multistep process making this tumor a candidate for chemoprevention. To date, retinoids are the best-studied chemopreventive agents achieving mixed clinical results in superficial bladder tumors. The potent apoptosis-inducing retinoid fenretinide is currently in the phase III trials. The follow-up of patients with all types of superficial tumors must be lifelong; unfortunately cystoscopy cannot be replaced yet by the control of any markers present or not in the urine. There is hope this may change in the near future.

Transdermal electromotive multi-drug administration for Peyronie's disease: preliminary results.

The purpose of this study was to clarify the actual therapeutic potential of a new transdermal drug delivery system (electromotive drug administration; EMDA) for selected patients with Peyronie's disease. Forty patients with Peyronie's disease were treated by electromotive administration of the 3-drug association orgotein-dexamethasone-lidocaine in a double-blind, placebo-controlled, partial crossover study (study 1). Another 25 patients were treated by EMDA with a combination of verapamil-dexamethasone in an uncontrolled study (study 2). Treatment sessions lasted 20 minutes each and took place 3 times a week for 3 weeks with a current of 3 mA. Patients were assessed before treatment and at 1- and 3-month follow-up examinations. Assessments were based on sexual history, physical examination, and dynamic color Doppler ultrasonographic results. Adverse effects of EMDA were not reported. In study 1, the clinical results observed after treatment proved to be significantly better than those of the placebo. Penile pain disappeared in all patients in both studies. Penile lesion (nodule or plaque) either disappeared or significantly improved in 79% and 90% of patients treated by the 3- and 2-drug association, respectively. The improvement of penile deformity also was notable although it did not match the effect observed on penile nodules or plaque (62% and 88%, in studies 1 and 2, respectively). In both studies, more than 80% of patients reported a definite amelioration of penile rigidity, which paralleled the improvement of penile dynamic color Doppler ultrasonographic parameters. Overall, the combination of verapamil-dexamethasone achieved better clinical results than the 3-drug combination. Electromotive drug administration is a novel technique capable of safely achieving satisfactory results in selected patients with Peyronie's disease not only in terms of improvement of patient's symptoms but also due to the reduced need for penile surgery.

Percent of free serum prostate-specific antigen and histological findings in patients undergoing open prostatectomy for benign prostatic hyperplasia.

PURPOSE: To determine which pathologic features of the surgical specimen in men undergoing open prostatectomy for benign prostatic hyperplasia (BPH) correlate with preoperative and postoperative total, free prostate-specific antigen (PSA) levels and the free-to-total PSA ratio. METHODS: Forty-four patients, undergoing open prostatectomy for BPH without evidence of prostate cancer in systematic biopsies and clinical prostatitis, were included in this prospective study. Each prostatectomy specimen was weighed and each slide was evaluated for inflammation (acute prostatitis, chronic-active prostatitis and chronic-inactive prostatitis), prostatic intraepithelial neoplasia, transitional/squamous metaplasia, cystic ductal dilation, leiomyoma-resembling stromal cell proliferation, leakage of prostatic secretion, infarction and prostatic calculi. RESULTS: The mean preoperative (and postoperative) total PSA and free PSA levels were 6.1 +/- 4.3 (1.14 +/- 0.87) and 1.7 +/- 1.6 (0.24 +/- 0.19) ng/ml, respectively. The mean prostatic and transition zone volume was 83.9 +/- 28.4 and 55.4 +/- 27.6 cm(3), respectively. Both total PSA and free PSA levels were correlated with total gland volume (p = 0.0001; p = 0.002) and the volume of the surgical specimen (p = 0.003; p < 0.05) and, upon stepwise logistic analysis, patients with a total gland volume of <50 cm(3) had an odds ratio of 11 (CI 1.6-71.3) for having a free-to-total ratio of <18%. No minimal change pathology or prostatic inflammation were associated with preoperative total or free PSA levels. The free-to-total PSA ratio was higher in the group of patients with histologically acute and moderate to severe chronic-active prostatitis (mean ratio 27 +/- 12%) than in patients with chronic-inactive prostatitis and minimal chronic-active prostatitis (mean ratio 0.19 +/- 13%; p = 0.05), showing an odds ratio of 5 (CI 1.1-22.1) for having a free-to-total PSA ratio of <18%. CONCLUSIONS: Prostate volume and, in particular, transition zone volume seem to influence both free and total PSA levels in men with BPH. The free-to-total PSA ratio seems to be influenced by the presence of histological prostatitis in the surgical specimen. In particular, patients with a prostate volume of <50 cm(3) and an inactive form of prostatitis seem to have a relatively higher risk of having a free-to-total PSA ratio of <18%.

Significance of bladder biopsies in Ta,T1 bladder tumors: a report from the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder Committee.

OBJECTIVES: We investigated to what extent biopsies of normal-appearing urothelium taken from patients with Ta,T1 bladder cancer showed malignant disease: carcinoma in situ, or papillary tumor. We also investigated biopsies underlying the papillary tumor, adjacent to the tumor, and from suspicious-appearing mucosa. METHODS: In EORTC protocol 30863 (low-risk tumors), 393 patients underwent a biopsy of normal-appearing urothelium. In protocol 30911 (intermediate- and high-risk tumors), multiple biopsies were taken from normal- appearing urothelium in 602 patients. RESULTS: No abnormalities were found in the random biopsies of 376 (95.6%) patients with low-risk tumors and in 532 (88.4%) patients with intermediate- and high-risk tumors. Six (1.5%) patients with low-risk tumors and at least 21 (3.5%) patients with higher-risk tumors showed carcinoma in situ in their random biopsies. None of the patients in the low-risk group and 1 (0.2%) patient in higher-risk group had an invasive tumor (T2). CONCLUSIONS: This analysis indicates that biopsies of normal-appearing urothelium in Ta,T1 bladder cancer patients show no abnormalities in about 90% of the patients. Performing such biopsies does not contribute to the staging or to the choice of adjuvant therapy after transurethral resection.