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.

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.

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.

High dose epirubicin is effective in measurable metastatic prostate cancer: a phase II study of the EORTC Genitourinary Group.

39 hormone-resistant prostate cancer patients with bidimensionally measurable metastatic lesions were given epirubicin 100 mg/m2 intravenously every 3 weeks. One patient was ineligible and excluded from analyses. According to WHO criteria, 9 patients (24%) had a partial response, 16 patients (42%) had stable disease (including 3 patients (8%) with a partial response not confirmed 1 month later), 11 patients (29%) had progressive disease, and in 2 patients (5%) response was not evaluated. Toxicity was as expected. Fifty-five per cent of patients had WHO grade 3/4 toxicity for white blood cells, and 3% of patients grade 3 toxicity for platelets. Other toxicities included nausea and vomiting, mucositis and alopecia. 2 patients with pre-existing cardiac disease developed cardiotoxicity (1 grade 2, 1 grade 3). An attempt was made to correlate response with prostate specific antigen (PSA) measurements. A positive trend was seen, but 2 non-responding patients showed a > 50% decrease in value.

Morbidity of modified pelvic lymphadenectomy and radiotherapy for prostatic cancer.

The records of 63 patients treated by pelvic lymphadenectomy and radiotherapy at the University of Tennessee, Memphis, Baptist Memorial Hospital of Memphis, and the Memphis Veterans Affairs Hospital were reviewed. Of those patients, 45 received external beam radiation therapy to the prostate while 16 were treated by Iodine-125 implantation. Two patients had only staging lymphadenectomy. The incidence of postoperative and late complications were analyzed.

Progression and complications after external beam radiation therapy for carcinoma of prostate.

Sixty patients with prostatic carcinoma localized to the pelvis have been treated by external beam radiation therapy: 2 patients (2%) were Stage A, 12 (20%) Stage B, 14 (23%) Stage C, and 32 (53%) Stage D1. Twenty-two patients received adjuvant therapy (11 estramustine phosphate [Estracyt] and 11 cyclophosphamide [Cytoxan]) after radiation. Progression occurred in 22 patients (37%): 6 (10%) had local recurrence while 16 (27%) failed distally. The incidence of late major complications was 12 percent.

Local seeding of anaplastic carcinoma of prostate after needle biopsy.

We present the seventh case of perineal localization of anaplastic carcinoma after needle biopsy of the prostate. The patient first had cryosurgery and bilateral orchiectomy followed by hormonal therapy (estrogens) and chemotherapy. The surgical excision of the mass was performed, but he died a few days later of metastatic disease.

Dose response relationship of methotrexate in combination with cisplatin in murine bladder cancer.

Methotrexate (MTX) has activity in transitional cell carcinoma (TCC) in man and some have suggested an advantage of high-dose methotrexate versus the standard dose in controlling tumor growth and prolonging survival. MBT-2, a poorly differentiated TCC induced by the carcinogen FANFT, is both grossly and histologically similar to human TCC and has been used as an animal model. One hundred twenty C3H/HE female mice were injected in the hind limb with 7.5 X 10(4) MBT-2 tumor cells. When palpable tumors developed in all animals, therapy was initiated. Animals were randomized into a control group and nine treatment groups as follows: cisplatin (DDP), MTX32 mg, MTX50 mg, MTX80 mg, DDP + MTX32, MTX50 + Leucovorin, MTX80 + Leucovorin, DDP + MTX50 + Leucovorin, DDP + MTX80 + Leucovorin. The combination of MTX50 mg with Leucovorin + DDP and DDP alone were the two most effective regimens in controlling tumor growth and prolonging survival. No statistically significant difference was observed between the group treated by high-dose MTX alone and those treated by low-dose MTX. No toxicity was observed even when high doses of MTX were used.

Comparison of single agent cisplatin and cisplatin containing combinations in treatment of murine bladder cancer.

Using the FANFT-induced tumors MBT-2 and MBT-683 we compared the response rate and survival using cisplatin alone and in various combinations with doxorubicin hydrochloride (Adriamycin), mitomycin C, methotrexate, and vinblastine. Sixty C3H/He female mice received 7.5 x 10(4) MBT-2 cells in the right hind limb. The animals were randomly divided into a control group and four treatment groups as follows: cisplatin, 6.0 mg/kg; cisplatin, 2.0 mg/kg, vinblastine, and methotrexate; cisplatin, 2.0 mg/kg, vinblastine, methotrexate, and doxorubicin hydrochloride; and cisplatin, 2.0 mg/kg, vinblastine, methotrexate, and mitomycin C. The drugs were given intraperitoneally on days 7, 14, and 21. The study was repeated using MBT-683. Drug effect on tumor diameter and survival were compared. Cisplatin alone was as effective in MBT-2 and more effective in MBT-683 in reducing tumor volume and increasing survival than the various combinations. The higher tolerable dose of cisplatin used as a single agent probably accounts for these results and suggests that cisplatin is the most effective agent in these combination therapy regimens.

Recombinant alpha interferon in metastatic renal cell carcinoma. A cooperative phase II study.

A total of 61 evaluable patients with advanced renal cell carcinoma have been treated with 3 x 10(6) IU per square meter of body surface with recombinant alpha 2b interferon three times a week within a Cooperative Phase II Study. Toxic death for terminal renal failure occurred in 1 patient (1.63%), and toxicities greater than WHO grade 2 were present in 10 cases (16%). The overall response rate after six months of treatment was 13.1% (partial response 4, minor response 4). Two complete responses were obtained at nine and fifteen months (3.3%). Long-lasting stabilization of disease was 13.1 percent.

Intravesical electromotive administration of drugs for treatment of superficial bladder cancer: a comparative Phase II study.

OBJECTIVES: To evaluate the efficacy of electromotive administration (EMDA) of intravesical mitomycin-C (MMC) in patients with superficial bladder tumors and to evaluate the toxicity of the treatment. METHODS: Thirteen patients with multifocal Stages Ta-T1 and G1-G2 transitional cell carcinoma (TCC) of the bladder, primary or recurrent (group A), received MMC 40 mg (retained in the bladder for 2 hours) once a week for 8 weeks. Fifteen patients with the same characteristics (group B) were treated with EMDA/MMC at a current of 15 mA for 20 minutes once a week for 8 weeks. All lesions in the bladder except one (marker) were resected in each patient. RESULTS: In group A, 5 of 12 patients (41.6%) demonstrated complete macroscopic and histologic disappearance of the marker lesion (complete response [CR]). In group B, 6 of 15 patients (40%) had a similar CR. Recurrence rate in responders was 60% in group A versus 33% in group B after 7.6 and 6 months, respectively. Disease-free interval was 14.5 months in the EMDA/MMC group compared to 10.5 months in the MMC group. Side effects were few. CONCLUSIONS: In intermediate risk patients with TCC of the bladder, EMDA/MMC was not superior to MMC alone with a CR rate of 41% versus 41.6%. In responders, a lower recurrence rate and a longer disease-free interval were observed in the EMDA/MMC group.

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.

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.

Expression of p53 protein in prostate cancers of different histologic types.

Mutations and overexpression of p53 gene in prostate carcinoma have been found but their significance in the development and progression of cancer is so far unknown. We investigated the prevalence of abnormalities of p53 protein in a heterogeneous group of prostate carcinoma to verify whether acinar and non acinar carcinomas have a different expression of p53 protein. Paraffin sections of 45 prostate carcinomas (39 acinar, 3 ductal papillary, 1 transitional cell, 1 mucinous and 1 pure small cell) were examined for the expression of p53 protein using a panel of antibodies (monoclonal antibodies Pab 1801, D07 and polyclonal antibody CM1). No p53 expression was observed in any acinar carcinomas independent of grade and stage. For non acinar carcinomas only small cell and transitional cell carcinomas exhibited detectable amounts of p53 protein in tumour cell nuclei. The prevalence of p53 overexpression in prostate carcinoma is relatively low compared with that found in many other tumours. In the present study, the overexpression of p53 in a small cell carcinoma and in a transitional cell carcinoma suggest that the loss of suppressing role of p53 gene may be an important mechanism in the genesis and in the development of these uncommon tumours.

[Primary transitional-cell carcinoma of the male anterior urethra]. / Carcinoma transizionale primitivo dell'uretra anteriore maschile.

Primary carcinomas of the male anterior urethra account for less than 1% of all urological carcinoma. The majority of these neoplasias develop of the posterior part of the urethra (proximal portion). The most common histotype is the squamous-cellular carcinoma. We have only found 4 other published reports of primary transitional carcinoma of the male anterior urethra. The paper discusses the diagnostic and therapeutic procedures employed in these rare cases.

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