A new long acting formulation of the luteinizing hormone-releasing hormone analogue goserelin: results of studies in prostate cancer.

PURPOSE: To assess the pharmacodynamic equivalence of the new 10.8 mg. goserelin depot with the current 3.6 mg. depot 3 studies were performed in patients with advanced prostate cancer. MATERIALS AND METHODS: In 2 comparative studies 160 patients were randomized for dosing every 12 weeks using the 10.8 mg. depot or every 4 weeks using the 3.6 mg. depot. In the noncomparative study 35 patients received the 10.8 mg. depot. Blood sampling for serum testosterone and evaluation of toxicity was done during the 48-week study period. RESULTS: Serum testosterone profiles of the 10.8 and 3.6 mg. goserlin depots were similar with testosterone levels decreasing into the castrate range by day 21 after depot administration. The safety profile of 10.8 mg. goserelin is comparable to that of the current monthly depot with the main side effects related to androgen deprivation. CONCLUSIONS: The new long acting depot was pharmacologically equivalent, and well tolerated locally and systemically, and will offer added convenience to patients and health care personnel.

Should random urothelial biopsies be taken from patients with primary superficial bladder cancer? A decision analysis. Members of the Dutch South-East Co-Operative Urological Group.

OBJECTIVE: To evaluate whether it is worthwhile to implement routine random biopsies from the normal-looking urothelium in the management of patients with primary superficial bladder cancer. PATIENTS AND METHODS: Two hypothetical management policies were compared, one of which incorporated random biopsies as an additional prognostic test. In the 'no-biopsy policy', all patients were treated with transurethral resection (TUR) alone, except for patients with a pT1G3 tumour who were treated with adjuvant prophylactic intravesical therapy. In the 'biopsy policy', the choice of treatment was influenced by the presence or absence of dysplastic urothelium in random biopsy specimens, except in patients with a pT1G3 tumour who received adjuvant treatment, irrespective of the result of random biopsies. Decision analysis was used to compare the outcome of these hypothetical policies with respect to the expected 3-year risks of recurrence and progression. Baseline data used in the analysis originated from a large unselected case series, prospectively documented in the Netherlands. RESULTS: The 'biopsy policy' resulted in a 3 year risk of recurrence and a 3 year risk of progression of 52% and 11%, respectively. These 3 year risks were almost identical to the 'no-biopsy policy': 54% and 11%, respectively. In a sensitivity-analysis, the expected 3 year risks of recurrence as well as the expected 3 year risks of progression were found to remain similar with both policies, even with quite extreme assumptions favouring the 'biopsy policy'. CONCLUSION: In view of the expected small difference in disease outcome between the two management policies, taking random biopsies of normal-looking urothelium at the time of the TUR has no practical value.

Dysplasia in normal-looking urothelium increases the risk of tumour progression in primary superficial bladder cancer.

Random urothelium biopsies were taken at initial endoscopic surgery from 1001 patients with primary superficial bladder cancer. The clinical course of all the patients was assessed prospectively. Actuarial risks of recurrence and disease progression were determined for prognostic characteristics and comparisons were made using log-rank tests. The independent prognostic significance of concomitant intra-aurothelial dysplastic changes was examined with Cox's regression analyses. The 3-year risk of recurrence in patients with dysplasia and carcinoma in situ (CIS) in macroscopically normal-looking urothelium was only slightly higher than the risk in patients without dysplastic changes (56, 58 and 51%, respectively; P = 0.25). Concomitant dysplasia or CIS significantly increased the 3-year risk of disease progression (17 and 31%, respectively, versus 7%; P < 0.001). After adjustment for the effects of age, tumour stage, grade, size and multicentricity, the result of random biopsies had no prognostic significance regarding the risk of recurrence, but the detection of dysplasia or CIS increased the risk of progression by approximately 80%. This result suggests that random urothelium biopsies may be useful as an additional guide in defining therapy in primary superficial bladder cancer.

Predictability of recurrent and progressive disease in individual patients with primary superficial bladder cancer.

The ultimate goal of prognostic assessment is optimization of individual counseling. Often, however, studies on prognostic factors focus on discriminating between high risk and low risk subgroups without considering the relevance of 1 or more factors for predicting disease outcome in individual patients. We quantified the accuracy of prediction of future recurrences and disease progression in individual patients with primary superficial bladder cancer. The study cohort consisted of 1,674 patients who were followed prospectively between 1983 and 1991 in the Netherlands. By analyzing half of the patients with proportional hazards regression, we computed relative risks of recurrence and progression. A prognostic index score based on these relative risks was then applied to the other half of the patients to determine whether group outcome could be predicted accurately. To assess the accuracy of prediction in individuals we used a method similar to the construction of receiver operating characteristic curves in diagnostic test assessment. The 3-year risk of first recurrence was 55% (95% confidence interval 51 to 59%). The 3-year risk of first progressive disease was 10% (95% confidence interval 8 to 12%). For the risk of first recurrence, tumor stage, tumor extent and multicentricity had statistically significant prognostic ability. Prognostic factors for the risk of disease progression were tumor stage, grade, multicentricity and the result of random biopsies from cystoscopically normal-appearing urothelium. For patients with a prognostic index score that suggested a low risk for recurrent and progressive disease the predicted 3-year risk of first recurrence was still 44% but the predicted 3-year risk of progression was only 3%. For patients with a prognostic index score that suggested a high risk the predicted risks were 74% and 22%, respectively. These predicted risks appeared to be fairly accurate when applied to the other half of our case series. However, in any 2 patients chosen at random the chance that the patient with the worst predicted prognosis would have a shorter recurrence-free and progression-free followup was calculated to be only 58% and 67%, respectively. Although the available prognostic factors in superficial bladder cancer may be useful to identify high risk and low risk subgroups, predictability in individuals is highly inaccurate. More relevant prognostic factors are needed to decrease current overtreatment and undertreatment rates, and to improve the followup policy.

The clinical epidemiology of superficial bladder cancer. Dutch South-East Cooperative Urological Group.

Even though the majority of patients with bladder malignancies initially present with low stage disease, the clinical epidemiology of these so-called superficial bladder tumours is not well known. In this paper, disease characteristics at initial presentation and during follow-up are described in 1,745 primary cases documented prospectively in the Netherlands. The risk of recurrent disease after primary treatment is very high: in 60% of cases, at least one recurrence is diagnosed within 5 years (95% CI: 58-62%). In patients with a small solitary pTa grade 1 tumour, the 3-year recurrence risk is 37%. In patients with multiple large high grade pT1 tumours, this risk is as high as 77%, despite a significant beneficial effect of adjuvant intravesical chemotherapy. The actuarial risk of disease progression is 10.2% after 3 years (95% CI: 8.6-11.8%). This risk of progression depends on the patient's age at diagnosis, tumour stage, grade, multiplicity and the presence of dysplasia or CIS in random urothelium biopsies. The use of intravesical instillations with chemotherapy or BCG vaccine after TUR does not prevent progressive disease, although this finding is difficult to interpret from a non-randomised study. The 5-year relative survival in patients with superficial TCC of the bladder is 86% (95% CI: 84-88%).