Randomized double-blind placebo-controlled multicenter evaluation of efficacy and dose finding of midodrine hydrochloride in women with mild to moderate stress urinary incontinence: a phase II study.

Midodrine is a potent and selective alpha1-receptor agonist and its potential to increase urethral closure pressure could be useful in the treatment of female stress incontinence. The aim of this randomized double-blind placebo-controlled multicenter study was to evaluate the efficacy and safety of midodrine for the treatment of stress urinary incontinence. The primary criterion of efficacy was the maximum urethral closure pressure at rest. Voiding diaries, symptom and incontinence questionnaires and patient/investigator global assessment were also used to evaluate its efficacy. After 4 weeks of treatment no significant changes in MUCP were found. The global assessment by the patient and investigator did indicate that patients on active treatment had a more positive assessment than the placebo group. In conclusion, midodrine did not cause significant improvements in urodynamic parameters, but there were subjective improvements in some of the patients in the treated groups. Furthermore midodrine was well tolerated.

Liarozole (R75251) in hormone-resistant prostate cancer patients.

BACKGROUND: Liarozole is an imidazole derivative that has been identified as an inhibitor of the cytochrome P450-dependent all-trans retinoid acid (RA) breakdown. RA is one of the principal endogenous compounds that controls growth and differentiation of epithelial tissues in mammals. METHODS: Fifty-five patients with hormone-resistant prostate cancer in progression, following at least first-line androgen ablation therapy, were evaluated. Thirty-one patients were treated with liarozole 300 mg b.i.d., while 24 patients started with 150 mg b.i.d., which was increased to 300 mg b.i.d. after 4 or 8 weeks. Two patients were not evaluable because they withdrew after initial consent. The WHO performance status was 0 (n = 18), 1 (n = 22), 2 (n = 17), and 3 (n = 6). Most patients (80%) used analgesics. RESULTS: For 11 out of the 53 patients, treatment lasted less than 1 month (they were therefore not evaluable for response) due to: poor compliance (n = 1); early death (n = 3); side-effects (n = 2); and decline of physical condition and continuous progression (n = 4). One patient refused to report for follow-up. In all responders, except one, the dose was increased to 300 mg b.i.d. In 23 of the 42 patients evaluable for response, the pain score improved. In 5 patients the pain score had reduced from 2 or 3 to 0. In 11 out of the 42 patients there was a 1-point improvement of WHO performance status. The prostatic-specific antigen (PSA) response rate was 41%; 15 out of 42 evaluable patients presented a decrease of > or = 50%, whereas PSA normalized in 2 further patients. Most of the side effects mimicked retinoid acid toxicity: cutaneous manifestations (such as dry skin, dry lips, sticky skin, brittle nails, erythema, or itch). All patients experienced one or more of these side effects. Other side effects include nausea, fatigue, and slight alopecia. CONCLUSIONS: Liarozole can be an enrichment of the therapeutic armamentarium for treatment of hormone-resistant prostate cancer patients after first-line androgen ablation therapy without serious toxicity.

Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. International Anandron Study Group.

PURPOSE: We studied the long-term efficacy and tolerability of nilutamide, a nonsteroidal antiandrogen, combined with orchiectomy in patients with advanced prostate cancer. MATERIALS AND METHODS: A large double-blind trial was done on 457 patients randomized to receive nilutamide or placebo after orchiectomy. RESULTS: At 8.5 years of followup significant benefits were found for progression and survival in favor of patients receiving nilutamide and orchiectomy. In addition, normalized prostate specific antigen levels at 3 months from the start of therapy were predictive of good long-term outcome. Moreover, combined androgen blockade with nilutamide increased the chance of patients having normal prostate specific antigen levels at 3 months. Nilutamide was well tolerated in the long term with no increase in the incidence of drug specific adverse events. CONCLUSIONS: With long-term followup of patients with advanced prostate cancer, the combination of nilutamide and orchiectomy has significant benefits in interval to progression and improved survival compared to orchiectomy and placebo.

Three-month depot of goserelin acetate: clinical efficacy and endocrine profile. Dutch South East Cooperative Urological Group.

OBJECTIVES: To compare the pharmacodynamics and tolerability of the new goserelin acetate 10.8-mg depot with the 3.6-mg depot in patients with advanced prostate cancer during the first 3 months of therapy. METHODS: One hundred sixty patients were randomized in two comparative studies to receive either the 10.8-mg goserelin acetate depot every 12 weeks or the 3.6-mg goserelin acetate depot every 4 weeks for 12 weeks and then the 10.8-mg depot every 12 weeks thereafter. Data for pharmacodynamic assessments were collected prospectively, whereas clinical response data were collected retrospectively. RESULTS: Serum testosterone profiles of the 10.8-mg goserelin acetate depot and the 3.6-mg goserelin acetate depot were similar; testosterone levels in both groups fell below castrate levels by day 21 after administration. Decreases in serum prostate-specific antigen level after 3 months of therapy were also similar in both groups: 94% with the 10.8-mg depot and 92.5% with the 3.6-mg depot. For all patients, the median time to progression was 152.7 weeks and the median time to death was 213.6 weeks. The safety profile of the 10.8-mg goserelin acetate depot was similar to that of the 3.6-mg depot; hot flashes was the most common adverse event. The incidence of injection site reactions was very low (2 [0.3%] of 614 administrations). CONCLUSIONS: The new 10.8-mg depot was pharmacodynamically equivalent to the current 3.6-mg depot and was well tolerated, both locally and systemically. The observed times to progression and survival were as expected in this patient population. The 10.8-mg goserelin-acetate depot provided a dosing schedule that was convenient for the patient and the physician, and it has the potential to reduce health care costs while maintaining the quality of life in patients being treated for advanced prostate cancer.

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.

Epidemiology of prostate cancer.

Prostate cancer is currently one of the most common malignancies worldwide. The incidence of prostate cancer has risen dramatically over the last decade, more so than can be explained by increasing longevity. Mortality rates have also risen, though not as dramatically. There is a wide geographic variation in the incidence of clinical prostate cancer, with higher rates in the United States than in China. One risk factor which could explain this variation is the high fat intake associated with a Western diet. It is also apparent that prostate cancer is now being detected at less advanced stages than in the past. Increased awareness of the disease and improved detection methods are thought to contribute to this earlier detection.

Advances and trends in hormonal therapy for advanced prostate cancer.

Hormonal therapy represents first-line treatment for patients with advanced prostate cancer. Generally, surgical castration is viewed as the 'gold standard' but carries with it a psychological effect. Medical alternatives include LHRH analogues, antiandrogens, and oestrogens, though the last of these is associated with cardiovascular problems. For complete androgen ablation, it is generally believed that androgens of both testicular and adrenal origin need to be blocked. Combined androgen blockade (CAB) by the addition of antiandrogen to castration (medical or surgical) may, therefore, be an appropriate treatment for advanced prostate cancer. Recent trials have shown that CAB may have treatment advantages compared with castration alone, and these benefits are greatest in patients with minimal metastatic disease. For these patients CAB may now be considered as standard therapy. In the treatment of non-metastatic disease, recent trends based on the experience gained in advanced prostate cancer include the possible use of hormonal therapy in neoadjuvant and adjuvant settings along with prostatectomy or radiotherapy. There is also growing interest in the use of intermittent rather than continuous hormonal therapy. New treatments offer an increasing range of management options to help improve the quality of life of prostate cancer patients.

Improved subjective responses to orchiectomy plus nilutamide (anandron) in comparison to orchiectomy plus placebo in metastatic prostate cancer. International Anandron Study Group.

Patients with advanced prostate cancer have a beneficial effect from maximal androgen blockade in terms of the subjective and objective delay of progression and median duration of survival, although side effects do occur more often in the combination treatment than in testicular suppression alone. Significant improvement or delayed deterioration in subjective parameters such as metastatic pain, performance status and urinary disorders strongly suggest (in the absence of validated questionnaires of quality of life at the time of this study) that orchiectomy plus nilutamide improves the quality of life as assessed by the subjective delay of progression, according to NPCP criteria, to an extent which outweighs the majority of adverse events.

A randomised trial comparing the safety and efficacy of the Zoladex 10.8-mg depot, administered every 12 weeks, to that of the Zoladex 3.6-mg depot, administered every 4 weeks, in patients with advanced prostate cancer. The Dutch South East Cooperative Urological Group.

A new longer-acting depot formulation containing 10.8 mg Zoladex administered every 12 weeks was compared to the 3.6-mg Zoladex depot administered every 28 days, in a randomised trial in patients with advanced prostatic carcinoma in which pharmacodynamic efficacy and safety were assessed. Effective induction of mean serum testosterone suppression into the surgically castrate range by 21 days and maintenance of suppression for the duration of therapy was achieved with both the 3.6-mg and the 10.8-mg depot formulations. The Zoladex 10.8-mg depot was well tolerated both locally and systemically. This new formulation which is equivalent to three successive 3.6-mg depots will provide a more convenient dosing regime for both patient and doctor in this indication.

Antitumoral effects of liarozole in androgen-dependent and independent R3327-Dunning prostate adenocarcinomas.

We examined the in vivo antitumoral effects of liarozole against androgen-dependent and independent Dunning rat prostatic tumors. Liarozole, applied as a dietary admixture, at a dose of 120 mg./100 gm. food, equivalent to 100 mg./kg. per day, inhibited the growth of the slow growing, well-differentiated, androgen-dependent Dunning-H tumor (median tumor volume decrease of 60%). At the same dose it also significantly reduced the growth of the androgen-independent, moderately differentiated PIF-1 (-60%) and androgen-independent, anaplastic AT-6 tumors (-73%). The growth of AT-6 sq tumor showing squamous metaplasia was unaffected by liarozole. When administered by oral gavage, liarozole at 40 (-82%) mg./kg. twice a day was as effective as castration (-92%) in reducing the androgen-dependent, poorly differentiated Dunning R3327-G tumor. Liarozole, administered by gavage, twice a day, also significantly reduced median tumor volume in the androgen-independent, AT-6 sq (-90% at 60 mg./kg., twice a day). This difference between liarozole administration by gavage and food admixture will have to be taken into account in further experimental studies. Inhibition of the growth of several androgen-dependent and, chiefly, androgen-independent Dunning prostate carcinoma sublines that differ widely in their histological degree of differentiation and growth rate suggests that liarozole may be a suitable agent for evaluation in second line treatment of hormone refractory prostate carcinoma in patients who relapse after androgen ablation.

A new extra long acting depot preparation of the LHRH analogue Zoladex. First endocrinological and pharmacokinetic data in patients with advanced prostate cancer.

A new depot formulation of the LHRH analogue Zoladex (goserelin acetate) has been developed which releases the drug over a period of at least 3 months as judged by measurement of drug content in depots at intervals after insertion in male rats and by the suppression of oestrogen secretion and oestrus in female rats. This formulation is based on the lactide/glycolide polymer system used for the standard 1-month Zoladex depot, but the dose has been increased to 10.8 mg and the characteristics have been modified to enable a longer release of drug to be achieved. Thirty-eight patients with histologically proven, locally advanced (stage T3 or T4) and/or metastatic prostate cancer were treated with this new longer acting LHRH analogue depot formulation containing 10.8 mg Zoladex. After initial increase of serum testosterone in the first week of therapy, castration levels were reached in all patients after 4 weeks and this was maintained for more than 14 weeks. At the time of depot exhaustion, when escape from castration levels of androgen occurred, all patients received a single injection of a standard 1-month depot containing 3.6 mg Zoladex which restored castration levels of androgen thus showing that the pituitary gland was again suppressed. The tolerance and acceptability of the longer-acting depot is high and comparable to the 1-month depot. Taking into account social and psychological factors, patients with advanced prostate carcinoma will soon be able to be treated with a longer acting LHRH depot formulation every 3 months an alternative of the 1-month depot now widely used clinically.

Analysis of prognostic factors in disseminated prostatic cancer. An update. Dutch Southeastern Urological Cooperative Group.

A statistical analysis of prognostic factors in 175 patients with hormonally treated disseminated prostatic cancer was done. The prognostic significance of performance status (PS), hemoglobin (Hb), alkaline phosphatase (Alk P), and testosterone was assessed with a univariate analysis. The authors did not find significant prognostic value in age, tumor size or grade, prostatic acid phosphatase, and prostate-specific antigen in these patients. In a multivariate logistic model (Cox regression), PS, Hb, and Alk P were found useful for dividing patients into prognostic groups. The prognosis for high-risk patients on standard hormonal treatment was very poor. The authors concluded that research on prognostic factors is useful and permits a division of patients into risk groups that makes choice of treatment more accurate. The use of new treatment combinations as a start treatment is appropriate for high-risk patients with disseminated prostatic cancer.

A new longer-acting LHRH analog depot: preliminary results of a Dutch open phase II clinical study on a 10.8 mg Zoladex 3-monthly depot.

A new longer-acting depot formulation containing 10.8 mg Zoladex was administered subcutaneously without anesthetic to 35 patients with advanced carcinoma of the prostate. Pharmacodynamic and pharmacokinetic data show that following a transient elevation in serum LH and testosterone, the levels of both hormones decrease. Serum testosterone reaches the castrate range in all patients by week 4 and remains at this level for at least 12 weeks. The serum Zoladex profile shows that castrate serum testosterone values can be sustained by very low serum concentrations of the drug of around 0.05 ng/ml. In this preliminary report, the efficacy and safety of this new longer-acting 3-month depot formulation of 10.8 mg Zoladex has been shown to be comparable to the 1-month depot formulation of 3.6 mg Zoladex, in patients with advanced carcinoma of the prostate.