Maximum androgen blockade using LHRH agonist buserelin in combination with short-term (two weeks) or long-term (continuous) cyproterone acetate is not superior to standard androgen deprivation in the treatment of advanced prostate cancer. Final analysis of EORTC GU Group Trial 30843. European Organization for Research and Treatment of Cancer (EROTC) Genito-Urinary Tract Cancer Cooperative Group.

This is the final analysis of EORTC GU Group Trial 30843 in which the treatment of advanced, metastatic prostate cancer with a combination of the LHRH agonist buserelin (nasal spray) and cyproterone acetate (Androcur), either continuously of only during the first 2 weeks, was compared with orchidectomy. There was no significant difference between the three arms as far as response rate, time to progression (subjective and objective) and duration of survival are concerned. Retrospective stratification according to the most important prognostic factors did not change the conclusions. Possible reasons for the difference with trial 30853, which used the same entry criteria but compared goserelin and flutamide with orchidectomy, are discussed. Reasons for using cyproterone acetate in combination treatment are the prevention of flare of the disease after LHRH agonists only and the prevention/reduction of toxicity in the form of hot flushes.

Short-term versus long-term addition of cyproterone acetate to buserelin therapy in comparison with orchidectomy in the treatment of metastatic prostate cancer. European Organization for Research and Treatment of Cancer--Genitourinary Group.

In an open, multicenter, three-armed, randomized study, we compared the effects of short-term (2 weeks) and continuous addition of the antiandrogen cyproterone acetate to the luteinizing hormone-releasing hormone agonist buserelin to those of orchidectomy in patients with advanced prostate cancer. No significant differences among the three treatment arms with respect to response rate, subjective response, time-to-progression, overall survival, and cancer deaths were observed. It was concluded that the short-term or continuous addition of cyproterone acetate to buserelin administered intranasally did not improve treatment results compared to orchidectomy only.

The position of cyproterone acetate (CPA), a steroidal anti-androgen, in the treatment of prostate cancer.

Cyproterone acetate is a steroidal anti-androgen that blocks the androgen-receptor interaction and reduces serum testosterone through its weak anti-gonadotropic action. It can be regarded as the only anti-hormone that causes complete androgen blockade as monotherapy. Many animal experiments and several clinical phase II and phase III trials have demonstrated that it deserves a place in the endocrine therapy of advanced prostate cancer, particularly for those patients who find orchidectomy unacceptable and who do not have known cardiovascular risks. Additionally, cyproterone acetate can be used safely to prevent disease flare when a luteinizing hormone releasing hormone analog is the drug of choice and to suppress hot flashes in response to LHRH agonists or after orchidectomy.

The use of the LHRH-analogue Buserelin in the treatment of prostatic cancer. A 10-year review on 1522 patients treated in 119 centres on 4 continents.

In the ten years from 1979-1988, a total of 1725 patients with advanced prostatic cancer were entered into 28 studies, in which Buserelin as a nasal spray was the main androgen deprivation therapy. Patients treated with orchiectomy or other anti-androgen agents used in comparative groups, were considered unsuitable for the purpose of this study, which pools the data of the 1522 patients who received Buserelin monotherapy. Patients with stages C, D1 or D2 prostatic cancer who received Buserelin as monotherapy and had a known treatment duration were eligible for efficacy analysis. The clinical evaluation was done in 91% by NPCP-criteria and in the remainder by criteria of the EORTC or ECOG. Seventy-five per cent of the patients received Buserelin nasal spray (3x daily 400 mcg), 20% received subcutaneous injections (2x daily 200 mcg) and 4% received 2 combinations of nasal spray, subcutaneous injections and depot, or depot alone. Compliance failures were found in 4.4% and 2.4% stopped treatment due to adverse reactions. Statistical analysis includes Kaplan-Meier estimates of time-to-progression and survival. Since 1985, after 2 patients died from possible fare reactions, anti-androgens have been recommended as additional therapy for the first few weeks. Features of this analysis of great interest are the national differences in progression-free survival and overall survival.

Orchidectomy versus Buserelin in combination with cyproterone acetate, for 2 weeks or continuously, in the treatment of metastatic prostatic cancer. Preliminary results of EORTC-trial 30843.

This prospective randomized phase III trial compares orchidectomy as standard androgen-deprivative therapy of advanced (metastatic) prostatic cancer with treatment using the LHRH agonist Buserelin administered as nasal spray 3 daily doses of 400 micrograms, and combined with cyproterone acetate (CPA) 3 daily doses of 50 mg orally for 2 weeks initially to prevent flare-up of the disease, or continuously as complete androgen blockade. The trial was closed to entry in September 1989 when 367 patients were recruited. Patients were stratified for performance status (WHO) and metastatic status prior to randomization. According to patient and disease characteristics spreading of patients over the 3 arms was without statistical significant differences. Ineligibility was 5 and 4% of the patients were only partly evaluable. In March 1990 a first, preliminary analysis was performed. At that time 207 patients were off-study for progression or death and median follow-up was 1 yr. As to time-to-progression and survival there were no significant differences between the 3 arms. The meaning of this in regard to results of other trials with complete androgen blockade is discussed.

The prognostic significance of selective nuclear morphometry in urinary bladder carcinoma.

Transurethral resected tumor specimens of 61 patients with a primary and untreated bladder carcinoma were studied by selective nuclear morphometry, a method recently described by us. A significant enlargement of the mean nuclear area was found with the advance of tumor grade and stage (Wilcoxon, P less than .0001 and P less than .0001). The heterogeneity of the grade 2 patient group and the additional value of morphometry were demonstrated by observing the 5-year survival rates. Patients with grade 2 carcinoma could be separated into one subgroup with small nuclei (mean nuclear area less than or equal to 95 microns2) having a favorable outcome (5-year survival rate: 100%), and into another subgroup with large nuclei (mean nuclear area greater than 95 microns2) showing a worse prognosis (5-year survival rate: 63.2%) (Mantel-Cox, P = .01). The outcome of these subgroups was not significantly different from that of the grade 1 (5-year survival rate: 93.8%) and grade 3 (5-year survival rate: 50%) patients, respectively (Mantel-Cox, P = .45 and P = .57). The value of selective nuclear morphometry, in addition to tumor staging, was indicated by the association of nuclear enlargement (mean nuclear area greater than 95 microns2) with progressive recurrence (five of 15 patients; 33%) among the patients with conservatively treated superficial carcinoma (stages Ta and Tl). The findings demonstrate the supplementary value of selective nuclear morphometry to tumor grading and staging, especially in the heterogeneous group of grade 2 carcinomas and the group of superficial tumors (stages Ta and Tl).

Reversibility of the effect of LHRH agonists and other antiandrogenic hormones on the testis: a histomorphometric study.

Changes in testicular morphology are quantified in patients with metastatic prostatic cancer, treated with LHRH agonist Buserelin and compared with testes of young transsexuals and patients with metastatic prostatic cancer treated with orchidectomy only. No significant changes within 18 months were seen, suggesting reversibility of LHRH agonist effects on testicular morphology in this time period. Histomorphometrics of the testis are useful to quantify these changes.

Morphometric and flow cytometric analysis of small cell undifferentiated carcinoma of the bladder.

Eighteen cases of primary small cell carcinoma of the bladder were studied. Three patients survived for two years and one survived for five years, which was significantly worse when compared with poorly differentiated transitional cell carcinoma (WHO grade 3). Aggressive tumour behaviour was independent of the presence of neuroendocrine characteristics. Morphometric analysis showed that the nuclear size, which was comparable with that reported in pulmonary small cell carcinoma, was significantly smaller than in poorly differentiated transitional cell carcinoma. Nuclear morphometry may therefore help identify small cell bladder carcinoma, especially in the absence of neuroendocrine differentiation characteristics. DNA flow cytometry of paraffin wax embedded specimens showed aneuploidy in 14 tumours--five were peritetraploid and two multiple aneuploid--and only three were diploid. Aggressiveness of small cell bladder carcinoma usually coincides with aneuploidy in most cases, but diploid tumours may also follow a rapid, lethal clinical course.

Small cell carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases.

A multiinstitutional review of 3778 patients with a primary malignancy of the urinary bladder revealed 18 cases (0.48%) of small cell carcinoma which were histologically and morphometrically identical to pulmonary small cell undifferentiated carcinoma. Age, sex, and symptoms at first presentation were comparable to that known in transitional cell carcinoma. Sixteen patients (89%) developed metastatic disease, with most frequent involvement of regional lymph nodes, liver, skeleton, and abdominal cavity. The unfavorable clinical outcome was worse as compared with that reported in advanced stage poorly differentiated transitional cell carcinoma, and was similar to the rapidly fatal outcome of pulmonary small cell undifferentiated carcinoma. Fourteen patients (78%) died by tumor at a mean follow-up period of 9.4 months, and only one patient was free of recurrent disease more than 5 years after cystectomy. This apparent aggressive tumor behavior was independent of the presence of neuroendocrine differentiation characteristics at immunohistochemical (13 cases, 72%) or electron microscopic study (eight cases, 44%). The prolonged survival periods (15-38 months) of the five patients who received combination chemotherapy suggested that, just as in small cell lung carcinoma, chemotherapy may be profitable. A unified concept of histogenesis of bladder cancer with a common origin from a multipotent mucosal stem cell is proposed.

Multivariate analysis of prognostic factors in patients with advanced prostatic cancer: results from 2 European Organization for Research on Treatment of Cancer trials.

The European Organization for Research on Treatment of Cancer Genitourinary Group performed a multivariate statistical analysis of prognostic factors based on 436 patients entered between 1976 and 1981 in 2 randomized prospective trials that compared 4 different hormonal treatment regimens. Only previously untreated patients with advanced (stage T3/T4/M0 or M1) prostatic cancer were eligible. After identification of prognostic factors by means of univariate analyses a multivariate analysis using Cox's proportional hazards regression model was done. This test identified performance status (according to the Eastern Cooperative Oncology Group scale) as the most important factor, followed by acid phosphatase (more than 2 times normal) for stage M0 cancer patients, and alkaline phosphatase, T category and the presence or absence of associated chronic disease for stage M1 cancer patients. Based on these 4 variables nonbedridden patients with metastatic disease can be divided into 2 groups: poor and good risk patients, with median survivals of 1 and 3 years, respectively. This study shows that routine clinical and laboratory data already provide an excellent indication as to the prognosis.

The value of morphometry and DNA flow cytometry in addition to classic prognosticators in superficial urinary bladder carcinoma.

In 80 patients with primary superficial bladder carcinoma Tumor Nodes Metastasis (TNM classification: stages Ta and T1) with adequate follow-up of at least four years, the value of selective nuclear morphometry and DNA flow cytometry on paraffin-embedded material in addition to classic prognosticators was assessed. Only the quantitative techniques appeared to be valuable predictors of new tumor occurrence. The recurrence rate in patients with large nuclei (mean nuclear area greater than 95 micron 2; n = 29) and in aneuploid cases (n = 30) was significantly higher (Wilcoxon: P = 0.05 and P = 0.0001) than in those with small nuclei (mean nuclear area less than = 95 micron 2; n = 51) and diploid cases (n = 50). The prevalence of large nuclei and aneuploidy also appeared useful to predict progressive recurrence, i.e., grade 3 or/and muscle invasive carcinoma (TNM classification: stages T2-T4) (chi-square: P less than 0.0001). Clinical follow-up showed that only 62.1% of the cases with large nuclei remained free of progressive recurrence, compared with 92.2% of those with small nuclei (Mantel-Cox: P less than 0.0001). For the aneuploid and diploid cases, these figures came to 53.3% and 98% (Mantel-Cox: P less than 0.0001). By multivariate analysis DNA ploidy was selected as the best discriminator. None of the classic prognosticators, including histologic grade, had additional prognostic value. Also, morphometry did not add to the prognosis prediction, which can be explained by the considerable overlapping between the prevalence of large nuclei and aneuploidy (24 of 29 and 30 cases, respectively). These findings practically suggest that patients presenting with superficial carcinoma with large nuclei (mean nuclear area greater than 95 microns 2) or aneuploid DNA values should be treated more aggressively.

Comparison of quantitative and classic prognosticators in urinary bladder carcinoma. A multivariate analysis of DNA flow cytometric, nuclear morphometric and clinicopathological features.

The prognostic value of nuclear morphometry and DNA flow cytometry of paraffin embedded material of 58 patients with primary and untreated transitional cell carcinoma of the bladder was compared with that of histological grade (WHO-system), tumour stage (TNM-classification), tumour size, multiplicity and ulceration. Small nuclear size (mean nuclear area less than or equal to 95 microns2) (n = 25) and DNA diploidy (n = 28) indicated a favourable outcome (5-year survival 95.8% and 92.2%); large nuclei (mean nuclear area greater than 95 microns2) (n = 33) and DNA aneuploidy (n = 30) indicated a worse prognosis (5-year survival 61.4% and 62.5%) (Mantel-Cox; p = 0.002 and p = 0.007). The quantitative techniques had the advantage over subjective histological grading that distinguishment of an intermediate patient group (WHO-system: grade 2; n = 32) with heterogeneous outcome (5-year survival 78%) was avoided. Multivariate analysis showed tumour stage as the most important prognosticator of survival. Neither the quantitative techniques, nor the other classic features added significantly to the prediction. The additional value of the quantitative techniques was however shown in superficial carcinoma (TNM-classification: stage Ta and T1; n = 37); large nuclei (mean nuclear area greater than 95 microns2) (n = 15) and aneuploid DNA peaks (n = 13) were associated with progressive recurrent tumour (n = 7) (Mantel-Cox: p = 0.03 and p = 0.0004). The quantitative methods thus indicate which patients are at risk for progression and may enable more appropriate treatment at an earlier stage of disease.

High energy shock waves do not affect either primary tumor growth or metastasis of prostate carcinoma, R3327-MatLyLu.

We investigated the possibility that extracorporeal high energy shock wave (HESW) treatment of solid tumors increased metastatic tumor cell spread using a rapidly metastasising rat prostate tumor variant (R3327-MatLyLu). Volume of HESW treated primary tumor, the volume of metastatic lymph nodes and the number of lung tumor nodules formed were compared with values in untreated control rats. HESW treatment resulted in marked hemorrhage and readily visible hematoma at the focal point of treatment. Tumor histology directly after treatment showed extravascular blood cells due to breakage of blood vessels. Contrary to previous reports we could not observe a delay in tumor growth rate in either small or medium sized tumors. More importantly the extent of metastatic spread was not influenced by HESW treatment.