Differential effect of finasteride on the tissue androgen concentrations in benign prostatic hyperplasia.

OBJECTIVE: The 5 alpha-reductase inhibitor, finasteride, provides a logical medical treatment for benign prostatic hyperplasia (BPH). However, the effects of chronic finasteride treatment on prostatic androgen levels, 5 alpha-reductase activity and tissue prostatic specific antigen (PSA) have not been studied. We have examined prostate tissue androgen concentrations and 5 alpha-reductase activity of the gland in men with BPH treated with the drug for 3 months. DESIGN AND PATIENTS: Twenty-eight patients with clinically diagnosed BPH, awaiting transurethral resection of the prostate, were entered in a double-blind placebo controlled study. Nineteen patients were randomly allocated to treatment with finasteride (5 mg daily) and 9 received placebo for 3 months. MEASUREMENTS: Prostate specimens were collected immediately following surgery and analysed for testosterone, dihydrotestosterone (DHT), androstenedione, 5 alpha-reductase activity and PSA. Blood specimens obtained before the start and immediately following treatment were also tested for steroid hormone concentrations and PSA levels. RESULTS: There was no significant difference in the median levels of intraprostatic testosterone (P = 0.77), DHT (P = 0.46) and androstenedione (P = 0.09) between the finasteride and placebo groups. However, the 5 alpha-reductase activity of the placebo group (237.9 pmol DHT/g tissue/30 min) was approximately 10 times that of the finasteride group (21.5 pmol DHT/g tissue/30 min; P = 0.0008). Although we were unable to detect any differences in the PSA concentrations of the prostate glands, there was a significant difference (P = 0.0002) in the median percentage change of serum PSA concentrations for the two patient groups. Serum DHT levels were also depleted (P = 0.038) whilst serum testosterone was increased (P = 0.054) in the finasteride patients when compared to the placebo group. Furthermore our study demonstrated no correlation between the in vitro 5 alpha-reductase activity of the gland and tissue DHT concentrations. CONCLUSIONS: Whilst finasteride treatment induced a reduction in serum dihydrotestosterone and prostatic specific antigen levels with a concomittant increase in blood testosterone concentrations, the impact of the drug on tissue androgen concentrations varied considerably from one patient to another. The differential effect of the drug on tissue androgen concentrations suggests that in the human prostate there are possibly more than one isoform of 5 alpha-reductase responsible for the accumulation of DHT in the gland.

Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients.

BACKGROUND: Controversy regarding the relative efficacy of treatments for the relief of the symptoms of benign prostatic hyperplasia (BPH). METHODS: This was a 6-month double-blind randomized equivalence study that compared the effects of a plant extract (320 mg Permixon) with those of a 5 alpha-reductase inhibitor (5 mg finasteride) in 1,098 men with moderate BPH using the International Prostate Symptom Score (IPSS) as the primary end-point. RESULTS: Both Permixon and finasteride decreased the IPSS (-37% and -39%, respectively), improved quality of life (by 38 and 41%), and increased peak urinary flow rate (+25% and +30%, P = 0.035), with no statistical difference in the percent of responders with a 3 ml/sec improvement. Finasteride markedly decreased prostate volume (-18%) and serum PSA levels (-41%); Permixon improved symptoms with little effect on volume (-6%) and no change in PSA levels. Permixon fared better than finasteride in a sexual function questionnaire and gave rise to less complaints of decreased libido and impotence. CONCLUSIONS: Both treatments relieve the symptoms of BPH in about two-thirds of patients but, unlike finasteride, Permixon has little effect on so-called androgen-dependent parameters. This suggests that other pathways might also be involved in the symptomatology of BPH.

Testosterone metabolism in primary cultures of epithelial cells and stroma from benign prostatic hyperplasia.

We studied the metabolism of testosterone in primary cultures of prostate epithelial cells and fibroblasts obtained from patients with benign prostatic hyperplasia (BPH). The conversion of 3H-testosterone in both cell cultures was predominantly to the oxidative pathway, with the formation of 3H-androstenedione increasing with cell number and time of incubation. Although we also detected some 5 alpha-reductase activity in these cells, the activity in the stroma component (0.00688 pmol/mg protein/min) was nonetheless insignificant when compared to the 5 alpha-reductase activity in the tissue of origin (0.0616 pmol/mg protein/min) and well below the 17 beta-hydroxysteroid dehydrogenase activity of the same cells (0.0518 pmol/mg protein/min). The aromatase activity in our cells was also measured by two separate techniques, but neither the deuterium procedure nor the production of oestrone from androgen precursors yielded any positive results, suggesting that under these experimental conditions there was no aromatase activity within the cells. The shift from the reductive to the oxidative pathways in these primary cell cultures was reminiscent of the androgen-metabolizing enzyme profiles seen in poorly differentiated prostate cancer. Whether this transition is an obligatory step in the development of hormone refractiveness remains to be elucidated.

Cytokine modulation of epidermal growth factor receptor expression on bladder cancer cells is not a major contributor to the antitumour activity of cytokines.

Epidermal growth factor is a potential mitogen for many different human tumours. Its effect is mediated via a bispecific receptor (EGFR), the expression of which correlates well with invasive disease. We investigated the modulation of EGFR by cytokines produced following bacillus Calmette Guerin (BCG)-immunotherapy. Our data demonstrate the IFN gamma, TNF alpha and IL-1 alpha can decrease the expression of EGFR on some bladder tumour cell lines. IFN gamma reduced EGFR expression on two of eight cell lines (RT4, SD). However, IL-1 and TNF did not share this activity. When cells were treated with a combination of all three cytokines, EGFR was decreased on three cell lines (RT4, RT112, SD) and furthermore, the change in the receptor expression was even more marked. Treatment with phorbol ester (thereby activating protein kinase C) resulted in rapid disappearance of the receptor from the cell surface. Interestingly, the decrease of EGFR expression did not require protein synthesis. Although the cytokines studied could down modulate EGFR, this only occurred on three out of eight cell lines; therefore, it is unlikely that the suppression of proliferative activity caused by cytokine-induced decrease of EGFR expression is central to the antitumour action of BCG therapy, but in a proportion of tumours this mechanism may be involved.

Interleukin-6 production by bladder tumors is upregulated by BCG immunotherapy.

PURPOSE: To determine whether BCG therapy could upregulate interleukin-6 (IL-6) production in human transitional cell carcinomas (TCC). MATERIALS AND METHODS: Immunohistochemistry of tumor biopsies and urinary cytospins and ELISA studies of urine from bladder cancer patients and TCC cell-line supernatants, before and after exposure to BCG, were performed. RESULTS: Constitutive staining for IL-6 was found in the majority of bladder tumors. Interleukin-6 was detected in the urine of all 13 patients with carcinoma in situ and increased 5-fold during BCG therapy. Levels were variable but were greater in nonresponders (p < 0.01). During therapy both detached bladder urothelial cells and polymorphonuclear leukocytes stained for IL-6. Production of IL-6 increased in only 3 cell lines after exposure to BCG, but all 7 cell lines showed increases after exposure to interferon-gamma (p = 0.015). Grade 3 cell lines showed much greater upregulation than grade 1 and 2 cell lines. CONCLUSIONS: The increase in IL-6 during BCG therapy may be caused by urothelial cells as well as leukocytes. The higher levels seen in nonresponders may be due to either higher grade or persisting tumor.

A case for synchronous reduction of testicular androgen, adrenal androgen and prolactin for the treatment of advanced carcinoma of the prostate.

The present study was undertaken mainly to investigate whether prolactin manipulation combined with maximal androgen blockage improves the effectiveness of treatment in advanced prostatic cancer. The efficacy of oral hydrocortisone as an alternative to commercial anti-androgens in reducing the adrenal androgens, and of bromocriptine in reducing the prolactin level were also examined. A consecutive series of 30 patients with untreated and advanced prostatic cancer were entered into a three-arm prospective randomised trial. 10 patients received subcapsular orchiectomy alone (arm 1), another 10 had subcapsular orchiectomy plus flutamide (arm 2), and the remaining 10 had subcapsular orchiectomy plus oral hydrocortisone and bromocriptine (arm 3). Clinical and biochemical parameters, including trans-rectal ultrasound-determined prostatic volumes, hormonal profiles and radionuclide bone scan were evaluated at regular intervals. At 12 months, serum testosterone was reduced by more than 90% in all arms, however, maximum suppression of androstenedione, prolactin, and reduction of prostatic volumes were only observed in arm 3; this was reflected by the significant improvement in clinical response in arm 3 compared with other arms. This study suggests that a combined maximal suppression of androgens and prolactin offers a significant improvement in response over conventional treatments without prolactin suppression in the treatment of advanced prostatic cancer. Importantly, a better clinical outcome in arm 3 was still apparent at the end of 36 months.

Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus Calmette-Guérin (BCG) immunotherapy.

Intravesical immunotherapy for carcinoma in situ of the bladder is arguably the most effective form of tumour immunotherapy described to date. Following repeated instillations of BCG organisms into the bladder, large quantities of cytokines are detected in patients' urine. This study concerns the production of IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and soluble ICAM-1 (sICAM-1) throughout the six weekly instillations which comprise a therapeutic course. Sequential instillations of BCG induced secretion of IL-1 beta, IL-2, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma and sICAM-1 into urine. The responses were heterogeneous between patients and cytokines, but some general trends were evident. Although cytokine levels were initially low, their concentration increased with repeated instillation of BCG. Certain cytokines (e.g. IL-6, IL-8 and IL-10) could be detected after the first instillation, whilst others (e.g. IL-2 and IFN-gamma) were not detected until after the third or fourth instillation. Interestingly, IL-4 was not detected, perhaps suggesting a differential effect on Th2-like responses. Some patients produced particularly elevated or non-detectable levels of cytokines, and a positive correlation was found between the production of various cytokines. The production of a particular cytokine did not correspond with lack of production of another species. Whether monitoring the production of cytokines following therapy may be of prognostic value will be determined in a larger series of patients. However, as these potent immunomodulators are thought to be important for the 75% complete clinical response observed with BCG therapy, there remains the possibility that detection of the products of an activated immune system may correlate with eventual clinical outcome. This study is a necessary forerunner to full prognostic evaluation of such immunological data.

Prostate disease: management options for the primary healthcare team. Report of a working party of the British Prostate Group.

The prostate gland has attracted a remarkable increase in interest in the past few years. The two most common diseases of this gland, benign prostatic hyperplasia and carcinoma of the prostate, have been brought into greater prominence by new diagnostic methods, public interest, and a wider choice of surgical and non-surgical treatments. Uncertainty about the significance of these changes has occurred because of the rapidity of change, the profusion of statements, opinions and promotions, and the relatively little guidance available from the profession. Ten urologists and two general practitioners have reviewed the relevant evidence about these two prostate diseases and the newer diagnostic methods; their conclusions are summarised here. Management options and guidance on clinical practice are also discussed. Because of a number of unresolved diagnostic and management issues, detailed requirements for practice guidelines have not been specified.

A radiofrequency method of thermal tissue ablation for benign prostatic hyperplasia.

OBJECTIVES: To evaluate the safety, feasibility, and efficacy of transurethral ablative prostatectomy (TURAPY), a radiofrequency method of thermal tissue ablation of benign prostatic hyperplasia (BPH). METHODS: Twenty men, ages 55 to 81 years (mean, 67), with symptomatic BPH and with peak flow rate 12 mL/s or less, were treated with the TURAPY device (Direx Medical Systems). A 2 cm long heating element and 2 thermoprobes (for simultaneous prostatic temperature monitoring) are mounted on a Foley-like catheter and used for TURAPY treatment administration. This TURAPY catheter was modified by placing an extra set of thermoprobes in the sphincter region to allow sphincteric temperature monitoring. The treatment was administered at a maximum temperature of 70 degrees to 75 degrees C for 1 hour under local anesthesia as a day case. RESULTS: All 20 patients completed the treatment. The maximum recorded rectal temperature was 39.5 degrees C. The maximum sphincter temperature was not allowed to exceed 42 degrees C. The post-treatment morbidity included dysuria and minor urethral bleeding in 12 patients. Three patients developed urinary infection requiring antibiotic treatment. All 20 patients were followed up 3 months after treatment. The mean International Prostate Symptom Score (IPSS) improved from 19.4 to 6.2 (68%), the mean peak flow rate increased from 7.9 to 12.9 mL/s (63%), and the mean postvoid residue decreased from 222 to 81 mL (64%). Overall, 80% of patients exhibited at least a 50% improvement in either the IPSS or the peak flow rate. There was a mean reduction in prostatic volume measured by transrectal ultrasound of 14 mL (29% reduction). The subjective and objective improvements, in 8 patients followed up 6 months after treatment, have been maintained. There was extensive coagulative heat necrosis of periurethral tissue with sparing of subcapsular tissue in prostate biopsy specimens taken from 1 patient 5 days after treatment. There was endoscopic and sonographic evidence of canalization of the obstructed prostatic urethra 3 months after treatment. CONCLUSIONS: Treatment with the TURAPY device was found to be safe, feasible, and effective in improving both subjective and objective measurements of benign prostatic obstruction in this pilot study on 20 patients.

Radical radiotherapy for localized adenocarcinoma of the prostate. A report of 191 cases.

OBJECTIVE: To assess the results of radiotherapy in the treatment of localized prostate cancer. End points for assessment were survival, local control, development of metastases, and the toxicity of therapy. MATERIALS AND METHODS: The case notes of 191 patients who were treated with radical radiotherapy between 1982 and 1992 were reviewed. The pathology of 130 patients was reviewed by a single pathologist. A multivariate analysis was performed to identify significant prognostic factors with regard to survival and relapse. RESULTS: One-hundred and eighty-two patients were assessable. The minimum length of follow-up was one year (median = 40 months). The actuarial cause-specific 5 and 10 year survival rates were 63% and 35% respectively. Local progression occurred in 41% of patients with 37% developing metastases. Multivariate statistical analysis demonstrated that T stage and Gleason Score were significant predictors for survival. Late complications were usually mild, with only 4% developing serious bladder toxicity. CONCLUSION: Radical radiotherapy has a role in the curative treatment of prostate cancer. Survival is significantly related to T stage at the time of presentation, and to the Gleason Score of the tumour. Survival in this series was not as good as the best surgical series, but it is still not clear which patients should receive radiotherapy and which surgery as their primary management.

Levels of circulating intercellular adhesion molecule-1 in patients with metastatic cancer of the prostate and benign prostatic hyperplasia.

Current reports suggest a role for intercellular adhesion molecule-1 (ICAM-1) in the progression of malignancy. The availability of a new antibody makes it possible to measure circulating ICAM-1 (cICAM-1) in human body fluids including serum; this might help in monitoring tumour burden and in providing additional prognostic information. In this study, serum levels of cICAM-1 were measured by an ELISA assay in patients with benign prostatic hyperplasia (BPH; n = 20) and metastatic cancer of the prostate (CaP; n = 25). Serum ICAM-1 concentrations were also measured in a group of healthy men (n = 8). The mean +/- S.E.M. cICAM-1 level for BPH was 339.52 +/- 15.30 ng/ml compared with 263.55 +/- 18.54 ng/ml for CaP. Even though the difference between the two groups was significant (P < 0.005), there was a marked overlap between the individual values in both groups, thus minimising the prognostic value of these measurements in prostate cancer. Endocrine therapy had no notable effect on the serum levels of cICAM-1. The mean +/- S.E.M. cICAM-1 concentrations in serum from a younger group of healthy volunteers was 204.1 +/- 10.38 ng/ml, and this value was significantly lower than that measured in serum from either BPH or CaP. We also undertook some immunohistochemical studies to examine the distribution of ICAM-1 in prostate tissue. We observed focal epithelial cell membrane staining which was exceedingly patchy in both the BPH and cancer specimens. On the basis of these studies, we suggest that cICAM-1 levels do not provide additional information on patients with metastatic CaP.

Conservative management with symptomatic treatment and delayed hormonal manipulation is justified in men with locally advanced carcinoma of the prostate.

OBJECTIVE: To examine the clinical course following surveillance and symptomatic treatment, and compare the outcomes of immediate and delayed hormonal treatment in men with locally advanced prostatic cancer. PATIENTS AND METHODS: Of a consecutive series of 199 men (mean age 74 years) with T2-T4 Nx M0 prostatic cancer, 110 (55%) were followed until death and the rest had a mean follow-up of 4.2 years. Fifty-one men received immediate orchidectomy, 88 had this treatment delayed until metastatic progression, and 60 had the treatment in the intervening period. The actuarial survival was compared with the expected survival for an age-matched healthy population in Scotland. The adjusted effect of the timing for hormonal manipulation was assessed by including it with age, Gleason score and clinical stage in a multiple Cox regression. RESULTS: The actuarial survival for the whole group was 17% less at 5 years and 15% less at 10 years when compared with the expected survival for an age-matched population in Scotland. This was despite the fact that their nodal status was unknown and also those with occult metastasis (elevated serum prostatic acid phosphatase, M1a) at presentation were not excluded. In terms of metastatic progression, overall survival and cause-specific survival, there was no significant difference between immediate and delayed hormonal treatment. CONCLUSION: A conservative approach with surveillance and symptomatic treatment for locally advanced prostatic cancer is justified by the present evidence on disease progression and survival, which do not differ from alternative methods of treatment as reported in contemporary literature. This study has the limitations relative to the ideal of a prospective randomized trial on immediate versus delayed hormonal treatment, but the lack of significant differences in outcome even after adjustment for other established prognostic factors does suggest that there may be little to be gained from an immediate orchidectomy.

The management of bilateral ureteric obstruction and renal failure in advanced prostate cancer.

OBJECTIVES: To investigate the effect of upper tract decompression on the prognosis of uraemia secondary to bilateral ureteric obstruction in prostate cancer, with particular reference to the hormone dependency of the tumour. PATIENTS AND METHODS: Prospectively collected data, over the period 1978-1993, were selected from the departmental database and from hospital case code data. Inclusion criteria were: blood urea > or = 15 mM, radiological evidence of bilateral ureteric obstruction, a histological diagnosis of prostate cancer, and the exclusion of out-flow tract obstruction. Of the 820 patients recorded in the departmental database, 27 (3.3%) fulfilled the criteria. Thirty-six patients were identified in total. Statistical analysis was by the Mann-Whitney non-parametric test. RESULTS: Of the 36 patients with bilateral ureteric obstruction and renal failure, in those in whom androgen depletion had been undertaken after ureteric obstruction (i.e. androgen depletion was a treatment option), the mean survival was 646 days (n = 12, SD = 786). Among these patients upper tract decompression improved survival and reduced the amount of time patients spent in hospital. In those in whom androgen depletion had been carried out before obstruction (i.e. the tumour had escaped from hormonal control), survival was significantly worse (80 days, n = 24, SD = 86.8, P < 0.01). In this group the use of decompression improved survival little. Percutaneous nephrostomy was the commonest means of decompression (nephrostomy, 9; stent, 5; ureteroneocystostomy, 2). DISCUSSION: In patients for whom hormonal therapy remains an option, upper tract decompression offers a worthwhile improvement in terms of increased survival and reduced in-patient time. However, if ureteric obstruction is diagnosed after hormone manipulation has been used, upper tract decompression has little effect on survival and should only be used in exceptional circumstances.

Air insufflation versus water irrigation during flexible cystoscopy: a prospective randomized study.

OBJECTIVE: To compare air insufflation with water irrigation during routine diagnostic flexible cystoscopy. PATIENTS AND METHODS: A total of 200 consecutive patients scheduled for routine diagnostic flexible cystoscopy under topical anaesthesia were randomized prospectively to either air insufflation or water irrigation. Their tolerance to the procedure and post-operative symptoms were assessed from a questionnaire completed immediately after the procedure and then 1 week later. RESULTS: Air insufflation offered a better cystoscopic view than water irrigation. With regard to tolerance, in the air insufflation group, 72% reported the procedure to be comfortable, 22% uncomfortable and 6% painful compared to 44%, 45% and 11% respectively in the water irrigation group. This difference in favour of air insufflation was highly significant (Chi-square, P < 0.001). There was no statistical difference in either post-operative symptoms a week later or in the diagnostic yield between the two study groups. There were no complications in either group. CONCLUSION: Air insufflation cystoscopy is as safe and effective as water irrigation but better tolerated by patients. This, together with its more obvious advantages of the ease of administration and low cost, should prompt more routine use of air insufflation cystoscopy for day case procedures.

Symptomatology of metastatic prostate cancer: prognostic significance.

OBJECTIVE: To identify the various presenting symptoms in patients with metastatic prostate cancer, quantify the metastatic load for each symptom group and compare their case-specific survival. PATIENTS AND METHODS: A prospective and consecutive series of 279 men with metastatic cancer of the prostate was analysed. Based on the symptom at presentation, six different groups were identified: bladder outflow obstruction, bone pain, anaemia, weight loss, paraplegia and alteration of bowel habit. RESULTS: Significant variations were observed in their metastatic load (Kruskal-Wallis test, P = 0.0035) and in case-specific survival (log-rank test, P = 0.0038). CONCLUSION: Bladder outflow obstruction, bone pain and anaemia not only dictate treatment selection but we provide evidence that each of these symptoms has considerable prognostic significance in patients with metastatic cancer of the prostate.

Induction of ICAM 1 expression on bladder tumours by BCG immunotherapy.

AIMS: To determine the expression of intercellular adhesion molecule 1 and 2 (ICAM 1 and 2) in transitional cell carcinoma cells before and after immunotherapy with Calmette-Guérin bacillus (BCG). METHODS: Frozen sections from 22 untreated bladder carcinomas were immunohistochemically examined with monoclonal antibodies to ICAM 1 and 2. Urinary cytospin slides were made for six patients for each of the six clinical instillations which constitute a therapeutic course. These slides were also stained for ICAM 1 and for leucocyte function associated antigen 1 (LFA 1). RESULTS: Bladder cancer cells did not essentially express either ICAM 1 or 2, but cells in the stromal areas surrounding tumour expressed both these antigens. After repeated instillations of BCG organisms ICAM 1 positive normal and neoplastic epithelial cells were observed in the urine. Cells obtained from the first three instillations expressed lower densities of ICAM 1 than those from the later instillations. Many neutrophils expressing LFA-1 and some lymphocytes were also noted in the cytospin slides and some of these were conjugated to tumour cells expressing ICAM 1. Six months after treatment a single maintenance dose of BCG induced ICAM 1 expression. CONCLUSION: Untreated superficial bladder carcinoma cells do not express ICAM 1 or 2, but these important immunological molecules were expressed in the stromal areas of tissue. Importantly, neoplastic cells in the urine expressed ICAM 1 after immunotherapy. This molecule can render bladder tumour cells vulnerable to non-antigen specific cytotoxicity mediated by activated lymphocytes.

Cystometrography provides a previously unrecognized opportunity for successful management of urinary leaks after renal transplantation.

We report 3 cases of urinary leakage occurring in male kidney transplant recipients within 6 weeks of renal transplantation. Voiding cystometrography showed that high voiding detrusor pressure was the contributing factor. Endoscopic bladder outlet surgery restored normal detrusor voiding pressure and led to spontaneous resolution of urinary leakage without recurrence in all cases.

A preliminary investigation of temperature distribution in the prostatic urethra during Thermex II thermotherapy.

In a random group of five patients undergoing thermotherapy with Thermex II (Direx Systems), the temperature in the region of the external sphincter was measured using a modified Thermex catheter. In all five patients the measured temperature exceeded 44.5 degrees C for more than half the duration of treatment. Further temperature mapping studies and studies on the assessment of sphincter function after Thermex II thermotherapy are in progress.