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L Denis

Publications and source records attributed to L Denis.

At least 37 records · Page 2Linked to original sources
PubMed1998

Liarozole--a novel treatment approach for advanced prostate cancer: results of a large randomized trial versus cyproterone acetate. Liarozole Study Group.

OBJECTIVES: To compare the efficacy of oral liarozole, the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors, with that of cyproterone acetate (CPA), an antiandrogen for the treatment of metastatic prostate cancer. Liarozole promotes differentiation of cancer cells by increasing the intratumoral levels of retinoic acid. METHODS: A total of 321 patients with metastatic prostate cancer in relapse after first-line endocrine therapy entered a Phase III international multicenter study (recruitment from February 1992 to August 1994) comparing liarozole (300 mg two times daily) with CPA (100 mg two times daily). RESULTS: Accounting for differences in baseline prognostic factors, the adjusted hazard ratio for survival was 0.74 in favor of liarozole (P = 0.039), indicating a 26% lower risk of death than in patients treated with CPA. Median crude (unadjusted) survival time was the same in the liarozole group as in the CPA group (10.3 months). More patients showed a PSA response (at least 50% reduction in PSA from baseline) when treated with liarozole (20%) than with CPA (4%) (P < 0.001). Prostate-specific antigen (PSA) responders had a median survival benefit of 10 months over nonresponders, irrespective of treatment (hazard ratio 0.43; P = 0.0018). PSA response was apparent within 3 months in approximately 90% of patients who responded. Pain improved more in the liarozole group than in the CPA group (P = 0.03). PSA responders had lower median pain scores than nonresponders (1.7 versus 2.5) and better quality of life (median Functional Living Index-Cancer score 108 versus 98) at end point, ie, treatment discontinuation, as well as throughout the treatment period. Among the most frequently occurring adverse events in the liarozole group were dry skin (51% of patients), pruritus (25%), rash (16%), nail disorders (16%), and hair loss (15%). These adverse events were generally mild to moderate in severity and did not affect the overall quality of life score. There were no detectable effects of either treatment on vital signs such as blood pressure, heart rate, electrocardiogram, and body weight. CONCLUSIONS: Liarozole is superior to CPA in terms of PSA response, PSA progression, and survival, and is capable of maintaining patients' quality of life. The observed adverse events were mild to moderate in nature. These results show that liarozole is a possible treatment option after first-line endocrine therapy has failed.

Aged↗
PubMed1998

Phytoestrogens and diseases of the prostate gland.

Both benign hyperplasia (BPH) and cancer of the prostate are manifest in men beyond the age of 50. Approximately 50% of men greater than 50 years of age will suffer from the symptoms associated with BPH, especially from bladder outlet obstruction. With the ever-increasing proportion of the population over 65 years of age worldwide, BPH is becoming an important medical problem as the world moves into the next millennium. Cancer of the prostate is the second most commonly diagnosed cancer after skin cancer in the male population of the United States, and the second most common cause of death from cancer after that of the lung. Overall, around the world the incidence of carcinoma of the prostate is increasing annually by 2-3%. Both race and geographical location have a profound influence of the prevalence of prostate cancer worldwide. Black men in the USA have the highest incidence, while the incidence is much lower in Asian men from China, Japan and Thailand. Although the prostate gland is androgen-dependent, it is now recognized that the biological actions of endocrine-related factors, such as androgens, oestrogens, glucocorticoids and certain dietary and environmental factors, are mediated within the gland by various growth regulatory factors. The growth regulatory factors such as epidermal growth factor (EGF), keratinocyte growth factors (KGF), fibroblast growth factors (FGFs) and insulin-like growth factors II and I are mitogenic and directly stimulate cell proliferation under the modulating influence of steroid hormones. Steroids are therefore essential but not directly responsible for cell proliferation. Certain plant compounds such as isoflavonoids, flavonoids and lignans have been proposed as cancer protective compounds in populations with low incidences of prostate diseases. In particular, soya contains the isoflavone genistein, a compound with many properties which could influence both endocrine and growth factor signalling pathways.

Estrogens, Non-Steroidal↗
PubMed1998

Early clinical experience with liarozole (Liazal) in patients with progressive prostate cancer.

Liarozole (Liazal) is the first retinoic acid (RA) metabolism blocking agent (RAMBA) in clinical practice. RAMBA therapy promotes differentiation and inhibits proliferation by increasing endogenous RA in tumours. Liarozole was investigated in two open-label pilot studies of 100 patients with progressive prostate cancer in relapse despite previous androgen ablation. Liarozole (150-300 mg twice daily, for > or = 1 month) produced > or = 50% reduction in prostate specific antigen (PSA) serum levels in 15 of 30 evaluable patients in study 1 (50%) and 10 of 55 patients in study 2 (18%). PSA responders had more marked reductions in prostatic acid phosphatase, alkaline phosphatase and symptom scores for bone pain and urological symptoms, and improved general well being. Plasma levels of adrenal androgens did not alter during chronic treatment with liarozole nor at adrenocorticotrophic hormone (ACTH) stimulation test. Liarozole did not alter plasma levels of adrenal androgens or cortisol. Cortisol response to ACTH stimulation was slightly blunted. Liarozole was generally well tolerated. Dermatological adverse events were probably related to increased intracellular RA. Liarozole appears to be a promising treatment option in prostate cancer.

Aged↗
PubMed1998

Surgery or radiation: is there really a choice for early prostate cancer.

One of the most difficult tasks for the practicing urologist is to counsel the patient in a decision for the optimal treatment for his localized prostate cancer. After providing the patient with contemporary and unbiased information and data, it is important to find the preferred treatment based on his age, the medical realities and, last but not least, the patient's personal preference. Radical prostatectomy, radiotherapy and observation are standard treatment options. TRUS-guided brachytherapy and cryosurgery are considered investigational treatment options since follow-up is inadequate to provide sufficiently precise outcome estimates. The literature does not provide clear-cut evidence for the superiority of any one treatment. The patient most likely to benefit from radical prostatectomy would have a relatively long life expectancy, no significant surgical risk factors and a preference to undergo surgery. The major advantage of radical prostatectomy is its potential for total removal of the cancer and cure in properly selected patients. Potential harm includes urinary incontinence and impotence. The patient most likely to benefit from radiation therapy would have a relatively long life expectancy, no significant risk factors for radiation toxicity and a preference for radiotherapy. The advantages of radiotherapy are that it has a potential for cure and it is well tolerated in the majority of men when the modern techniques are used. Potential harm includes radiation cystitis, proctitis and impotence, persisting severe complications are only seen in 1% of patients. The patient most likely to benefit from surveillance are those with a shorter life expectancy and/or a low grade tumour. Benefits are lack of treatment related morbidity with only marginal compromise of disease-specific survival at 5-10 years follow-up.

Humans↗
PubMed1998

Casodex 10-200 mg daily, used as monotherapy for the treatment of patients with advanced prostate cancer. An overview of the efficacy, tolerability and pharmacokinetics from three phase II dose-ranging studies. Casodex Study Group.

OBJECTIVES: To evaluate the efficacy, tolerability, endocrinological effects and the pharmacokinetics of Casodex, when given as monotherapy during daily dosing of 10-200 mg to patients with advanced prostate cancer. METHODS: A total of 390 patients with advanced prostate cancer were treated for a minimum of 12 weeks with a daily monotherapy dose of Casodex. The doses ranged from 10 to 200 mg. Objective assessments of efficacy included: review of measurable metastases, prostate dimension, prostatic acid phosphatase and prostate-specific antigen (PSA) levels. Subjective assessments of efficacy included review of urological symptoms, performance status, bone scan and analgesic requirement. Pharmacokinetic samples were taken at various time points up to 3 months, and assayed using an achiral HPLC method. RESULTS: Clear objective responses were observed, particularly at doses of 50 mg and above. Specifically, the median percentage decrease in PSA at 50 mg was 90.0%, and at 100 and 200 mg it was 93.4 and 94.8%, respectively. Up to 53% of symptomatic patients demonstrated a subjective response at 3 months. Casodex was well tolerated at all doses with no effect on haematological or cardiovascular parameters and no effect on renal function. The expected pharmacological effects of potent antiandrogen therapy, such as breast tenderness (58%), gynaecomastia (48%), and hot flushes (17%), were reported, but these incidences reflected the direct eliciting of these events. The intrinsic efficacy of Casodex was demonstrated despite increases of 60% in testosterone levels. However, this increase reached a plateau after 4-12 weeks of therapy, but the majority of values remained within the normal range. Casodex has a half-life of approximately 1 week, enabling once-daily dosing with no effect of age or renal impairment on its pharmacokinetics. CONCLUSION: Casodex has a favourable side effect profile compared with the known safety profiles of other antiandrogens and has demonstrated intrinsic efficacy. Casodex warrants further investigation as a monotherapy for the management of advanced prostate cancer.

Acid Phosphatase↗
PubMed1998

The importance of prognostic factors in the interpretation of two EORTC metastatic prostate cancer trials. European Organization for Research and Treatment of Cancer (EORTC) Genito-Urinary Tract Cancer Cooperative Group.

INTRODUCTION AND OBJECTIVES: The EORTC conducted two randomized phase III trials of maximal androgen blockade (MAB) in 695 patients with metastatic prostate cancer. Trial 30,843 compared orchidectomy or buserelin to buserelin plus cyproterone acetate and showed no significant difference in survival while trial 30,853 showed that Zoladex plus flutamide had a significantly longer survival than orchidectomy. Reasons for this discrepancy were sought. METHODS: In order to determine whether differences in patient characteristics could explain these possibly contradictory results, a Cox proportional hazards regression model was used to identify prognostic factors for survival in each study. Patients were divided into risk groups (good or poor prognosis with 3.5 and 1.75 years' median survival, respectively) based on their alkaline phosphatase, hemoglobin, performance status, pain score, T category and G grade at entry on study. RESULTS: The survival advantage of MAB in 30,853 was limited to patients with a good prognosis (164/302 (54%) of the patients). In 30,843, only 93/337 patients (28%) had a good prognosis so there were insufficient data to draw separate conclusions in these patients. Despite the limitations of subgroup analyses, these results show that patients in 30,843 had on the average a worse prognosis than patients in 30,853. Hence there were fewer good prognosis patients who could potentially benefit from MAB, thus providing one possible explanation for the overall negative conclusion. CONCLUSIONS: These studies once again underline the importance of taking into account patient characteristics when designing and interpreting metastatic prostate cancer trials. They also provide criteria which may be used to define risk groups as part of a protocol's patient eligibility criteria. In the design of future trials assessing MAB, a sufficient number of good prognosis patients should be entered to reliably assess treatment efficacy in this subgroup.

Aged↗
PubMed1998

Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer.

Prostatic cancer is the second most common cause of cancer death in males. Treatment by radical prostatectomy and radiotherapy is useful in the early stages of the disease. Whenever metastases occur, patients are usually treated by surgical (orchidectomy) or medical [gonadotropin releasing hormone (GnRH) analogue] castration. This form of treatment is, however, associated with unwanted adverse effects, such as flushing, loss of libido and potency and all patients ultimately escape therapy after a delay of 1 to 2 years. For this reason antiandrogens have been developed as another means of endocrine ablation therapy. Antiandrogens fall in 2 groups of which the first group, the steroidal antiandrogens such as cyproterone acetate (CPA), have a direct blocking effect at the cellular level but also inhibit testosterone production by their additional gestagenic properties blocking gonadotropin secretion. Except in preventing the flare-up associated with the start of GnRH analogue therapy and in reducing flushing, no evidence exist of any superiority for CPA over classical therapy in terms of adverse effects and survival. The second group, the nonsteroidal or 'pure' antiandrogens, only block androgens at the cellular level without any central effects. In contrast with other forms of castration, patients on pure antiandrogens as monotherapy preserve their sexual function and potency, at the expense of a slightly inferior androgen blockade and gynecomastia. These latter effects are explained by a compensatory rise in androgens as a result of the blockade at the central level, which weakens the androgen blockade, and by peripheral aromatisation of the increased androgens to oestrogens. In addition, some evidence exist that pure antiandrogens improve survival if combined with other forms of castration as they also inhibit the adrenal androgens, the so-called maximal androgen blockade (MAB). If patients escape control under MAB, a trial of stopping the antiandrogen must always be considered, as some tumours have 'learned' to be activated by these drugs. At the moment it is not yet clear if antiandrogens are of any benefit in downstaging the extent of disease before prostatectomy and/or radiotherapy. Of the currently known pure antiandrogens, bicalutamide offers some advantages over flutamide as it possesses a much longer half-life, allowing a once daily regimen, and has advantages over nilutamide in terms of fewer adverse effects.

Androgen Antagonists↗
PubMed1997

Prostate volume and cancer in screening programs.

BACKGROUND: Prostate cancer screening is studied in a randomized trial in Antwerp, Belgium. The case group receives three screening tests (DRE, TRUS, and PSA). Intermediate evaluation shows that only 1/3 of the biopsy results is positive (35/125). The proposed analysis identifies variables that determine the biopsy outcome. METHODS: Multiple logistic regression analysis is used to regress biopsy results (n = 125) by age (60-74), PSA, PSA-D, prostate volume, TRUS, and DRE. Continuous variables are transformed into quartile values. Robustness of the outcome is tested with ROC and sensitivity analysis on age. RESULTS: Biopsy outcomes are best explained (82.3%) by PSA, DRE, and DRE related to volume. Volume is more sensitive than age to explain the biopsy result. PSA-D, instead of PSA, does not procure more precise information when a high PSA cut-off level is used. Restricting the analysis to the 60-70-year-old age group shows that volume is more sensitive. ROC-analysis confirms the findings. CONCLUSIONS: When performing prostate cancer multitest screening among a wide age range, the use of uniform screening criteria is difficult to accept due to differences in prostate volume. Logistic regression analysis is an appropriate method to identify cut-off levels for prostate volume.

Aged↗
PubMed1997

The European Randomized Study of Screening for Prostate Cancer: an update.

BACKGROUND: A consensus meeting on screening and global strategy for prostate carcinoma, held in Antwerp in 1994, determined the willingness among European cancer prevention centers to pursue vigorously the collaborative formation of a multinational randomized screening trial. This trial was to be named the European Randomized Study of Screening for Prostate Cancer (ERSPC). METHODS: During the years prior to that meeting, several feasibility trials were conducted in Antwerp and Rotterdam to evaluate the pitfalls and problems of a randomized procedure for population screening. Today, five centers in five European countries share their study work and results via the ERSPC, and others are lining up to join this massive effort. Regular meetings and specific work groups enable the research centers to compare their data, because the trial methodology differs slightly from one center to another. RESULTS: However, a common work strategy and analysis of the data has recently been reached, and the first study results of the trial (evaluating 180,000 men over a 10-year screening period) are expected by the year 2007. CONCLUSIONS: A randomized trial of prostate carcinoma screening is set up in Europe currently with five participating centers from five countries. First overall effect results of regular screening are expected after a 10-year period of follow-up.

Biopsy↗
PubMed1997

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.

Adult↗
PubMed1997

Planning controlled clinical trials. Prostatic cancer.

OBJECTIVE: To address principles in the design and conduct of clinical trials on prostate cancer (PC) with special reference to localized disease. METHODS: In advance of and during the World Health Organization (WHO) conference on Prostate Cancer in Stockholm in September 1996, 6 members of a working group evaluated and reached consensus on key points for the planning and conduction of controlled clinical trials in PC. The key points discussed were 1) hypothesis formulation, 2) general methodological principles, 3) special problems of PC trials, 4) alternatives to randomization, and 5) trial organization. RESULTS: The hypothesis must be clearly formulated and also clinically relevant enough to justify the expenses (in a broad sense) of a randomized clinical trial. Patient selection, definition of endpoints, and sample size calculations must be carefully considered and correspond to the aims of the study. Stratification on important prognostic factors should be contemplated. Maintaining the accrual rate and ensuring compliance are critical for a quality study. Survival is the main endpoint and intention to treat analysis is the standard methodology. Secondary endpoints (eg, quality of life and costs) are important for the evaluation of many treatment modalities. The use of surrogate endpoints for survival, such as prostate-specific antigen (PSA) elevation, may be misleading. Surrogate endpoints require further validation. Special features, such as long natural history in localized disease and difficulties in assessing objective responses in advanced disease, need consideration in PC trials. The controlled randomized trial is the gold standard methodology. Nonrandomized trials are often hampered by severe methodological problems, such as selection bias and biased ascertainment of endpoints due to the doctor's or patient's preferences. For the organization of a successful trial, a well-constructed study protocol is essential. Good clinical practice as defined within the European Community helps define and solve practical problems. CONCLUSIONS: The past 30 years of poorly designed clinical research on PC has left us without reliable answers in key clinical issues regarding, for example, the efficacy of primary treatment of localized PC. It is a stimulating and important challenge to the urological scientific community to conduct well-organized controlled clinical trials.

Controlled Clinical Trials as Topic↗
PubMed1997

[Prevention and treatment of erectile disorders in sickle cell disease].

Priapism is a frequent and serious cause of morbidity in males with sickle cell disease. Acute priapism (AP) is preceeded in two-thirds of the cases by repeated minor events called stuttering priapism (SP). Since 1994, we have used a specific approach to prevent the commonly devastating effects of AP, using the alpha adrenergic agent etilefrine. Treatment of AP has been simplified (drainage without aspiration followed by one or two intracavernous injections (ICI) of 10 mg of etilefrine, until detumescence). For SP lasting more than one hour or causing pain, we use oral etilefrine and/or self ICI. This strategy was effective in five patients seen having AP, 21 patients with SP; it is simple, cheap, and avoids surgical procedure and transfusion. Moreover, erectile dysfunction, present in three patients, has been treated safely by ICI of protaglandins.

Adolescent↗
PubMed1996

The quality of life of patients with newly diagnosed M1 prostate cancer: experience with EORTC clinical trial 30853.

This study was undertaken to evaluate the quality of life (QoL) of previously untreated patients with M1 prostate cancer before and during androgen-suppressive treatment. Assessment of QoL was included as an optimal component of EORTC protocol 30853, a phase III trial comparing LH-RH (luteinising hormone-releasing hormone) analogue combined with a non-steroidal anti-androgen versus orchiectomy in patients with M1 prostate cancer. At pretreatment and during the follow-up period, patients were asked to complete a questionnaire assessing their physical and psychosocial functioning, and their symptom levels. Physicians rated the patients' performance status, pain, urological symptoms and erectile function. Due to its optional nature, only a minority of the patients in the trial were recruited for the QoL investigation. 63 patients completed a pretreatment questionnaire, of whom 49 completed a second questionnaire at least once during the initial 15 month follow-up period. While statistically significant correlations were observed between patients' and physicians' ratings of physical functioning and pain, these were of only a moderate magnitude (r = 0.43 and 0.30, respectively). No significant association was observed between physicians' and patients' ratings of micturation problems or of erectile function. Before treatment, fatigue, pain and decreased social role and sexual functioning were the problems most frequently reported by patients. With an average of approximately 1 year follow-up, statistically significant improvements were observed in patients' self-reported urological symptoms and metastatic pain. No significant changes were noted for the other QoL domains assessed. The results of this study confirm earlier findings that physicians' ratings may not reflect accurately the functional health and symptom experience of their patients. Patient-based QoL questionnaires offer the most direct means of evaluating the subjective morbidity associated with prostate cancer and its treatment. To increase participation and compliance rates in future studies, it is recommended that QoL assessment be made mandatory in those clinical trials in which QoL is considered to be an important study endpoint.

Aged↗
PubMed1996

Pharmacodynamics and pharmacokinetics of bicalutamide: defining an active dosing regimen.

Bicalutamide, a potent nonsteroidal antiandrogenic drug devoid of hormonal agonist activity, is considered to be a pure antiandrogen. Binding of bicalutamide to the androgen receptor results in regression of prostate tumors. The antiandrogenic activity resides exclusively in the R-enantiomer. The S-enantiomer of bicalutamide is rapidly cleared, but the R-enantiomer has a plasma elimination half-life of about 1 week, with a tenfold plasma accumulation at all dose levels, making it suitable for a once-daily administration. It has been shown that plasma concentrations increase linearly with dose after either single or multiple dosing. These pharmacokinetics are not affected by age, impairment of renal function, or mild-to-moderate hepatic impairment. Following daily administration of single doses of 50 mg/day for 12 weeks result in steady-state plasma concentrations for the R-enantiomer of +/- 9 micrograms/mL. A single dose of 50 mg/day was preferred because this dose resulted in a 50% decrease of prostatic acid phosphate (PAP) in 83% of the treated patients. Subsequent studies focused on the decrease of prostate-specific antigen (PSA) as a surrogate endpoint. Decreases of PSA of > or = 90% were noted with daily doses of 100-200 mg. The excellent safety profile allows further investigations of doses up to 450 mg daily. Studies are ongoing to establish the most efficient dose with acceptable levels of toxicity in order to maximize the effect of bicalutamide on clinical response, time to progression, mortality, and quality of life.

Androgen Antagonists↗
PubMed1996

Chemoresection in Ta-T1 bladder cancer. Members of the EORTC Genito-Urinary Group.

OBJECTIVES: The authors present the results of two parallel phase II trials, instituted by the EORTC Genito-Urinary Group in 1986, whose aims were to assess the tolerability and ablative capacity of mitomycin C (study 30864) and epirubicin (study 30869) in patients with multiple primary or recurrent Ta-T1 bladder cancer. METHODS: A well-defined tumour (marker lesion) was left in the bladder after transurethral resection (TUR). All patients received 8 weekly instillations, after which cystoscopy with bladder biopsies +/- TUR was performed. Responses were rated as follows: (1) complete-no visible or microscopic bladder cancer; (2) no change-persistence of the marker lesion; (3) progression-increased marker lesion size, new tumour(s) or presence of muscle-invasive disease at any site. RESULTS: Ninety-six evaluable patients were treated with mitomycin and 36 with epirubicin. The overall bladder response in the former group was complete in 50%, no change in 30% and progression in 20% of patients, while the marker lesion response was complete in 57%, no change in 39% and progression in 4%. In the epirubicin group, 56% of the patients achieved a complete overall response, while there was no change in 22% and progression in 22%. The marker lesion response in this group was complete in 67%, no change in 31% and progression in 3%. Only 2 cases of progression were due to the presence of muscle-invasive disease. Both of these were in the mitomycin group; 1 was at the marker lesion site, and 1 was at a remote site. CONCLUSIONS: The present studies confirm the feasibility and safety of the marker lesion model for the objective evaluation of the antitumoural activity of intravesically administered drugs.

Administration, Intravesical↗