Fritz H. Schroeder

Treatment of Benign Prostatic Hyperplasia by Androgen Deprivation: Effects on Prostate Size and Urodynamic Parameters

The possible effect of medical androgen deprivation in the treatment of benign prostatic hyperplasia has been studied in 12 patients. Six patients received the luteinizing hormone-releasing hormone agonist buserelin and 6 others received the antiandrogen cyproterone acetate. The treatment resulted in an average decrease in prostatic size of 29 per cent after 12 weeks as measured by ultrasonography. This decrease led to an increase in peak urinary flow rate, a reduction in residual urine volume and a decrease in daytime voiding frequency. However, it caused no decrease in urethral resistance but only an increase in the bladder contraction strength. After discontinuation of the treatment the prostates showed regrowth to the initial sizes within 6 to 36 weeks. The urodynamic changes were reversed as well. Although statistically significant, the urodynamic changes were minimal from a clinical viewpoint and did not lead to an unobstructed state after 12 weeks of treatment. For this reason the clinical indication for use of medical androgen deprivation in benign prostatic hyperplasia patients will remain limited for the time being.

Monoclonal Antibody KI-67 Defined Growth Fraction in Benign Prostatic Hyperplasia and Prostatic Cancer

Growth fractions were assessed immunohistochemically in prostatic tissues with benign glandular hyperplasia (BPH) and in specimens of prostatic cancer using the monoclonal antibody Ki-67. This antibody is specific for a proliferation-associated nuclear antigen. In BPH tissues about 0.3% of nuclei of epithelial cells was reactive with Ki-67. The Ki-67 positive nuclei were distributed equally among the basal and luminal cells of the hyperplastic prostatic acini. In prostatic cancer the Ki-67 defined growth fraction ranged from 0.4% to 9.1% (mean value 2.9%). Cancers with a cribriform growth pattern and tumors composed of solid areas of undifferentiated cancer cells showed the highest growth fraction (average values 4.0%, respectively 7.6%). The investigated four tumors composed of undifferentiated solitary tumor cells with diffuse infiltration of the stroma demonstrated an unexpectedly low growth activity (average 1.2%). In cancers with a glandular growth pattern the Ki-67 defined growth fraction of tumor cells varied from 2.2% to 5%. Compared with other epithelial tumors these values are low, but they are in agreement with the earlier findings on prostatic cancer obtained with 3H-thymidine labeling and bromodeoxyuridine incorporation. The observed variation in the level of Ki-67 defined growth activity partly related to the histological tumor pattern suggests that Ki-67 labeling may serve as a prognostic factor additional to the current histopathological grading criteria of prostatic cancer.

Serum retinal and prostate cancer

Levels of retinol, beta carotene, and alpha tocopherol were assayed by high performance liquid chromatography (HPLC) in serum from subjects with clinical prostatic cancer (n = 94), focal prostatic cancer (n = 40), benign prostatic hyperplasia (n = 130), and from hospital controls (n = 130). Levels of beta carotene and alpha tocopherol varied for prostatic cancer patients by disease stage and by the period in the treatment sequence when blood was collected. This made any assessment of their association with prostatic cancer risk difficult. The mean level of serum retinol was significantly lower (P < 0.05) in prostatic cancer patients than in the controls. For serum retinol this difference did not appear to be attributable to age, stage of disease, period in which the blood was collected, or to several other potentially confounding factors. When the serum retinol level was considered in quintile classes, there was a statistically significant (P < 0.05) trend of increased prostatic cancer risk associated with decreasing serum retinol levels.

Benign prostatic hyperplasia treated by castration or the LH-RH analogue buserelin: a report on 6 cases.

This article presents the clinical data of 5 patients treated by castration and 1 patient treated with an LH-RH analogue to relieve chronic urinary retention due to benign prostatic hyperplasia (BPH). Besides the clinical data related to prostatism, prostatic volume was studied in 4 of the 5 patients by means of transrectal ultrasonography. All 5 patients showed a marked decrease of prostatic volume, which averaged 31.4% (range 19-55%) after 2-3 months. This correlated well with a relief of urinary obstruction. In all 5 patients, the indwelling catheters could be removed, symptoms decreased or disappeared and all 5 patients became free of residual urine. LH-RH analogues, because of the reversibility of their effect, may be more acceptable for the treatment of BPH than castration. At this moment however, it remains unknown whether prostatic volume will increase again after cessation of androgen withdrawal.

Metastatic Cancer of the Prostate Managed with Buserelin Versus Buserelin Plus Cyproterone Acetate

We recruited 71 previously untreated patients with metastatic prostatic carcinoma to 2 separate consecutive prospective phase 2 studies done by the same group of investigators according to the same protocols in which only the treatment regimens differed. Of the patients 58 were treated with the luteinizing hormone-releasing hormone analogue buserelin alone (0.4 mg. 3 times daily intranasally) and 13 were treated with buserelin combined with cyproterone acetate, a potent antiandrogen (50 mg. 3 times daily orally). The objective of the study was to investigate the efficacy, safety and tolerability of the medication used during at least 12 months by studying adequate endocrine parameters, the rate and duration of response, as well as the rate of progression and possible side effects. All endocrine parameters were studied in 1 laboratory. Modified response criteria of the National Prostatic Cancer Project were used. The endocrine studies showed an effective suppression of plasma testosterone to castration levels by buserelin after an initial increase during the first 2 weeks. Luteinizing hormone and follicle-stimulating hormones were lowered significantly and could not be re-stimulated by the intravenous application of luteinizing hormone-releasing hormone. There was no correlation of plasma testosterone with response and progression. However, a significant correlation existed between higher basal cortisol levels at entry, and after 3 and 6 months, and progression. Response is reported for all patients at the 12-month interval and did not seem to differ among treatment groups. The rate of progression after all patients had been treated for 1 year was 37.9 per cent in the buserelin group and 41 per cent in the buserelin plus cyproterone acetate group. Three early deaths occurred in the buserelin group. Except for impotence, only mild side effects were noted. Our study shows that treatment of metastatic prostatic cancer by means of the luteinizing-hormone-releasing hormone analogue buserelin is safe and effective. The results obtained are compatible with those obtained by castration. In our study a superiority of total androgen withdrawal over testicular suppression alone could not be shown.

Surgical Treatment of Locally Advanced (T3) Prostatic Carcinoma: Early Results

The fate of 48 patients with clinical stage T3 prostatic carcinoma after attempted curative surgical management was studied. In 23 of these patients positive frozen sections of the lymph nodes were found at pelvic lymphadenectomy and orchiectomy was performed. The median interval to progression was 61 months. Radical prostatectomy was performed in the remaining 25 patients. In 4 of these patients positive lymph nodes were found on paraffin sections but no additional treatment was given. Over-all, total tumor removal as defined by negative lymph nodes and negative margins of resection could be achieved in 14 of the 48 patients (29 per cent). During the same period 34 patients with clinical state T less than 3 prostatic carcinoma were treated in a similar manner. Orchiectomy was done in 4 patients because of positive frozen sections of the lymph nodes and radical prostatectomy was done in 30, including 1 in whom positive paraffin sections of the lymph nodes were found but no additional treatment was given. An attempt was made to study the impact of several prognostic factors by comparing the probability of progression between patients with stage pT3 disease with (T3pT3N0) or without (T less than 3pT3N0) extracapsular tumor growth as determined by preoperative rectal examination (36 versus 27 per cent progression at 3 years), with or without positive margins of resection (45 versus 20 per cent progression at 3 years) and with or without involvement of the seminal vesicles (47 versus 18 per cent progression at 3 years). Our results suggest that a certain proportion of patients with clinical stage T3 disease will benefit from radical prostatectomy. This is to be expected especially in patients with stage T3pT3N0 cancer and negative margins.

Urogenital tract abnormalities associated with congenital anorectal anomalies

Of 150 children with congenital anorectal malformations 50 per cent had urogenital abnormalities. Vesicoureteral reflux was noted in 47 per cent of the children with a supralevator and in 35 per cent with an infralevator lesion. A urinary tract evaluation is recommended in all children with congenital anorectal anomalies.

Physical characteristics and factors related to sexual development and behaviour and the risk for prostatic cancer.

A case-control study of prostatic cancer was carried out to examine the association between selected physical characteristics and factors related to sexual development and behaviour and the risk for this disease. In consideration of an endocrinologic mechanism for these putative risk factors, the association between selected factors and serum hormone level in a comparison group, free of prostate cancer, was also examined. One-hundred cases and 113 controls were included for study. An elevated risk for prostatic cancer was found for those currently married (odds ratio (OR) = 4.0), those who had been married once (OR = 2.8), and those who were currently practising a religion (OR = 2.0). Compared to subjects with one child, those with more than one child and those with no children were more common among cases than controls. Prostatic cancer risk was associated with large body size and, in particular, with greater weight (p < 0.01). Early age at attainment of adult height was also associated with prostatic cancer risk (p < 0.01). Only moderate associations were found between increased frequency of sexual intercourse and prostatic cancer risk. The levels of testosterone (T), dihydrotestosterone, salivary testosterone and T/SHBG (sex hormone binding globulin) did not vary with age. Older men had higher oestradiol levels. Further, little association between hormone levels and risk factors was found, except for married subjects having increased serum androgens (p < 0.05) and heavy subjects having decreased serum androgens (not significant).

Transrectal Ultrasonography in the Followup of Prostatic Carcinoma Patients

Prostatic volume was determined by transrectal ultrasonography before and after castration in 13 patients, and after radiotherapy in 24. Measurements were done after 1, 2 and 3 months, and subsequently at 3-month intervals. Significant volume reductions occurred in the castration and radiation groups within 3 months. The decrease in prostatic volume was significantly more pronounced in the castration group during the entire study (p less than or equal to 0.01). Patients with enlargement of the prostate predominantly owing to benign prostatic hypertrophy also had a decrease in volume. No increase in prostatic volume after initial reduction was encountered for up to 9 months. In several cases progression of metastases occurred with no increase in the volume of the primary tumor. Followup may be too short to encounter local recurrence after radiotherapy or hormone-independent growth after castration. Proctitis after radiotherapy created artifacts that probably led to inaccurate measurements with ultrasonography. The technique provides a new, accurate parameter for followup of conservatively treated prostatic cancer patients. The clinical importance of the technique still remains to be determined.

Variation of prostate-specific antigen expression in different tumour growth patterns present in prostatectomy specimens

SummaryA series of 55 randomly chosen radical prostatectomy specimens was analyzed for expression of prostate-specific antigen (PSA) by immunohistochemical techniques. Tissue sections were selected in such a manner that in addition to glandular benign prostatic hyperplasia (BPH), one or more different prostatic tumour growth patterns were present. Four monoclonal antibodies, directed against three different PSA epitopes, and one polyclonal anti-PSA antiserum were used. Expression of PSA was compared with that of prostate-specific acid phosphatase (PAP), recognized by two different polyclonal antisera. A critical dilution aimed at a maximum of staining intensity on BPH tissue sections was chosen for all antibodies. Anti-PSA and anti-PAP antisera stained essentially all BPH samples (over 90%). Irrespective of the nature of the antibodies used, PSA expression was found to be decreased in prostatic carcinoma. A clear cut relationship was found between immunoreactivity for PSA and the degree of differentiation of the tumour area. Under the experimental conditions used the PSA monoclonal antibodies stained only 1 out of 10 undifferentiated carcinomas, whereas 50% to 70% of the well- and moderately-differentiated carcinomas showed immunoreactivity. This correlation was less pronounced with the PAP staining pattern. If the PSA antibody titer was raised the percentage of clearly staining undifferentiated carcinomas could be considerably increased (up to 60%–100%), indicating that PSA expression is not absent, but lowered in most (if not all) undifferentiated carcinomas.