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Biomedical subjects

L Denis

Publications and source records attributed to L Denis.

At least 55 records · Page 3Linked to original sources
PubMed1995

Commentary on maximal androgen blockade in prostate cancer: a theory to put into practice?

The population at risk of prostate cancer is on the increase, and so is public awareness of this disease. There has been an unresolved controversy surrounding the benefits of maximal androgen blockade (MAB) as a valid approach to treatment of non-curative prostate cancer since it was first proposed in 1945. How are we to interpret the data on MAB in order to give each patient the best advice on treatment? Studies of MAB using medical castration (luteinizing hormone-releasing hormone [LHRH] analogue plus antiandrogen) vs. LHRH analogues alone are inconclusive when viewed collectively, although the largest showed objective benefits for MAB. The remaining studies have insufficient power to show the expected effect size. Studies of MAB using surgical castration plus antiandrogen vs. surgical castration alone also gave inconsistent results, although a meta-analysis is in favor of MAB on objective criteria of response. Among trials of MAB using an LHRH analogue vs. surgical castration alone, one is positive and the remaining two are neutral for MAB. No study shows MAB to be worse than either medical or surgical castration alone. An overall meta-analysis shows a trend for benefit with MAB but is not statistically significant. The existing data have strongly suggested that there may be a particular benefit for certain subgroups of patients (including those with minimal disease) but numbers studied have been too small to allow valid conclusions. The INT 0105 trial in progress may permit firmer conclusions to be drawn on this and other questions. In the meantime one of the drawbacks to current MAB regimens is the exchange of modest clinical advantages for the side effects of nilutamide and flutamide. Given that the disease is noncurative, improved quality of life is the main goal of therapy, and excellent tolerability of treatment is fundamental to this. In a comparative trial, bicalutamide (Casodex) was more effective than flutamide (each in combination with an LHRH analogue) in terms of time to treatment failure and produced a significantly lower incidence of diarrhoea. In conclusion, the evidence supports early use of adequate hormonal treatment, and this should mean either medical or surgical castration, ideally augmented by an antiandrogen. Tolerability of the antiandrogen is a key consideration in gaining an improvement in quality of life with MAB.

Androgen Antagonists↗
PubMed1995

Effects and systemic uptake of the new mitomycin C analogue KW-2149 in beagle dogs after intravesical administration.

The present study was designed to evaluate the local effects of the new mitomycin C analogue KW-2149 after intravesical instillation, together with its penetration into the systemic circulation in healthy beagle dogs. Two reference dogs were treated with two instillations of mitomycin C (30 mg in 30 ml phosphate buffer). Four dogs were given two, three, four and six instillations, respectively, of KW-2149 (60 mg in 30 ml phosphate buffer). KW-2149 concentrations measured in the systemic circulation were very low and were frequently found to be below the limit of determination. The number of instillations had no influence on the KW-2149 concentrations measured in the systemic circulation. Blood analysis showed no systemic toxicity. The histopathological findings in the bladder were comparable in both groups. The number of instillations had no influence on the severity of the lesions found in the bladder wall. On the basis of its in vitro activity KW-2149 can be regarded as a promising agent for intravesical treatment of superficial bladder cancer.

Administration, Intravesical↗
PubMed1995

Factors affecting recurrence and progression in superficial bladder tumours.

Prognostic factors in superficial bladder tumours are highly correlated with each other. In this study, their relative importance is examined and grouping of patients in three different prognostic groups suggested. 576 patients (from EORTC protocols 30790 and 30782) were analysed. They have been followed from 3 months to 8.6 years with a median of 4 years. 76 patients developed an invasive tumour (> or = T2); the shortest time to invasion was 12 weeks, the longest was 6.6 years. Time from invasion to death ranged from 3 weeks to 4.4 years with a median of 2 years. Prognostic factors contributing to recurrence, invasion and survival were investigated: age, sex, size of largest tumour, number of tumours, T-category, G-grade, time from diagnosis (years), prior recurrence rate/year, site of involvement. The relative importance of these factors was measured by performing a multivariate analysis based on Cox's proportional hazards regression model. Based on the most important prognostic factors and their association with invasion and death, an index was computed reflecting the risk of both invasion and death due to malignant disease, respectively. The index was used to assign patients to one of three prognostic groups. Three main factors determined patient's prognosis: tumour size, G-grade and prior recurrence rate/year. The model coefficients for invasion were 0.51 (recurrence rate < 1/year, 1-3/year, > 3/year), 84 (grade 1, 2, 3), 0.48 (size < 1.5, 1.5-3, > 3 cm) and for death due to malignant disease 0.89 (recurrence rate), 0.73 (grade) and 0.44 (size), respectively. Risk groups are suggested based on the index. Additional treatment in patients with superficial transitional cell carcinoma of the bladder may be decided depending on the risk group to which the patient belongs.

Adolescent↗
PubMed1994

Phase I trial of high-dose fosfestrol in hormone-refractory adenocarcinoma of the prostate.

Androgen deprivation displays the mean therapy of advanced stage prostatic cancer. The development of hormone-resistant disease leads to a fatal tumor progression. High-dose fosfestrol (diethylstilbestrol disphosphate) has been suggested to circumvent hormone resistance and to induce a direct cytotoxic effect. Twenty-one patients with hormone-refractory prostate cancer were enrolled in a phase I trial of continuous infusion of high, daily escalating dose of fosfestrol. Fosfestrol was given in a 3.5 hr infusion in 0.9% normal saline at a starting dose of 1.5 g/d. The dose was increased daily in the same patient according to the following schedule: 1.5, 1.8, 2.4, 3.0, 3.6, 3.9, 4.5, 5.1 and 5.7 g/d. The duration of the infusion was prolonged to 7 or 10.5 hr, if a major side effect occurred. There was neither hematological nor cardiovascular toxicity. The main dose-limiting toxicities were nausea/vomiting in 17 patients, edema in 2 patients, and more than 5% weight gain in 3 patients. The planned maximal dose was reached in 10 patients during a 3.5 hr infusion, and in 3 additional patients, after infusion prolongation. Seven patients experienced a subjective improvement: Prostatic acid phosphatase and prostatic specific antigen decreased in 4 out of 11 and in 7 out of 12 patients, respectively. The suggested dose to phase II trial is 4 g/d in 3.5 hr infusion for a duration of up to 10 days.

Acid Phosphatase↗
PubMed1994

Role of maximal androgen blockade in advanced prostate cancer.

Androgen ablation by bilateral orchiectomy or by the administration of gonadotropin-releasing hormone (GnRH) agonists has become standard treatment for advanced prostate cancer. However, serum levels of dihydrotestosterone (DHT) remain at about 40% of the precastration levels due to the conversion of the adrenal androgens. Maximal androgen blockade (MAB) aims to block the stimulatory action of this adrenal-derived DHT by adding antiandrogens to surgical or medical castration. Some of the largest and best controlled randomized trials in Europe and the United States have shown statistically better progression-free survival, overall survival, and survival from death by prostate cancer with MAB than with monotherapy with a GnRH agonist or with bilateral orchiectomy. Trial 30853 of the European Organization for Research and Treatment of Cancer (EORTC) compared MAB using a combination of goserelin subcutaneous depot (Zoladex; Zeneca Pharmaceuticals, Macclesfield, UK) and flutamide with bilateral orchiectomy. Some other published trials did not find the differences revealed by EORTC 30853, however, and so an overview or meta-analysis of trials on the effects of MAB was organized jointly by the American Cancer Society, the Urological Group of the EORTC, and the International Prostate Health Council. Preliminary results on some of the 23 trials included in the meta-analysis showed an advantage of the GnRH agonist therapy in combination with an anti-androgen, particularly in time to progression. If time to progression is viewed as improved quality of life due to the absence of symptoms, a net result in favor of the combination therapy is noted. The MAB trials, using flutamide as the antiandrogen, also showed a small but distinct improvement in survival with the combination treatment. An emphasis on prognostic factors allows treatment decisions to be reached more easily.

Combined Modality Therapy↗
PubMed1994

Endocrine profiles during administration of the new non-steroidal anti-androgen Casodex in prostate cancer.

OBJECTIVE: Casodex (Zeneca) is a new potent, long-acting non-steroidal anti-androgen, which produces androgen deprivation by blocking the androgen receptor. We evaluated the endocrine effects of Casodex 150 mg daily given in monotherapy as primary treatment for patients with prostate cancer. DESIGN: As part of a large, multicentre study comparing the therapeutic effects of surgical castration with 150 mg/day Casodex in monotherapy for patients with prostate cancer, a subgroup of 23 patients on Casodex were studied in detail for changes in endocrine parameters. Serum levels of LH, FSH, testosterone, DHT, oestradiol, prolactin, sex hormone binding globulin and free testosterone were measured at the start of therapy and after 1, 4, 8, 12 and 24 weeks. Effects on libido, sexual activity and the appearance of hot flushes, breast pain and gynaecomastia were recorded. RESULTS: Administration of Casodex resulted in a rise in LH levels in all patients with a mean increase after 24 weeks of 102% (P < 0.001). Mean FSH levels showed a limited increase (7%) after 24 weeks, which was significant only after 1 week (P < 0.001). As a result of the high LH levels, total testosterone levels increased after 24 weeks by 66% (P < 0.001), free testosterone by 57% (P < 0.001) and dihydrotestosterone by 24% (P = 0.0112). Parallel to testosterone, oestradiol levels rose by a mean of 66% (P < 0.001). Mean sex hormone binding globulin and prolactin levels rose by respectively 8% (P = NS) and 65% (P < 0.01). Despite an increase in testosterone levels, excellent androgen blockade was obtained, as shown by a decrease in prostate specific antigen levels in 22/23 patients. Libido was maintained in 8/11 patients, and sexual activity in 5/6. No patient complained of hot flushes. However, mild gynaecomastia and/or breast tenderness were seen in 48 and 30% of cases respectively. CONCLUSION: Casodex 150 mg/day monotherapy resembles surgical castration in achieving androgen deprivation, despite an increase in LH and testosterone levels. In contrast to castration, libido and sexual activity are usually maintained and hot flushes are rare. However, mild gynaecomastia and/or breast tenderness were noted in 48 and 30% of patients.

Aged↗
PubMed1994

Octreotide in advanced prostatic cancer relapsing under hormonal treatment.

Since somatostatin analogues have been shown to possess inhibitory activity on prostatic cancer cells in animal models, we studied the clinical effects of the long-acting somatostatin analogue octreotide in the treatment of advanced prostatic cancer. Five patients with metastatic prostatic cancer in relapse under hormonal treatment and with rapidly increasing levels of prostate specific antigen (PSA) received a subcutaneous infusion of octreotide in a dose of 400 to 1,000 micrograms/day for a period of 2 to 6 months. Patients were followed clinically and by monthly measurement of PSA levels. During treatment 3/5 patients showed a temporary halt in rising PSA levels, while another patient had a small decrease. This inhibitory effect however was lost after 1 to 3 months of therapy in 3 patients. The remaining patient died after 4 months before an escape of PSA levels was seen. Side effects consisted of mild diarrhoea in three patients. From this very preliminary data, it appears that octreotide in a dose of 400 to 1,000 micrograms/day may give only a moderate and temporary inhibition of tumor growth in patients with advanced prostatic cancer. Because of the limited effects the study was interrupted prematurely. Since higher doses, other somatostatin-analogues or the combination of LHRH analogues may give better results, further studies are needed to determine the potential therapeutic role of somatostatin-analogues in this group of patients.

Aged↗
PubMed1993

Orchiectomy versus goserelin and flutamide in the treatment of newly diagnosed metastatic prostate cancer. Analysis of the criteria of evaluation used in the European Organization for Research and Treatment of Cancer--Genitourinary Group Study 30853.

This European Organization for Research and Treatment of Cancer (EORTC) trial 30853 is the fifth EORTC--Genitourinary Group randomized phase III trial of endocrine treatment for patients with newly diagnosed metastatic prostate cancer. Special attention was given to the assessment of response and/or progression. Each of the following factors was assessed separately as nonspecific and subjective criteria of response or progression: performance status, pain, alkaline and acid phosphatase, hemoglobin, urinary symptoms, and prostate-specific antigen (PSA). Objective progression was based on measurable disease. The observed sequence of progression was: (1) protein-specific antigen; (2) bone; (3) pain; and (4) performance status. Protein-specific antigen, an optional parameter, was the first sign of progression in more than 50% of patients whose disease had progressed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Comparability of prostate trials.

The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type of antiandrogen (flutamide, Anandron, or cyproterone acetate) added to castration. This paper reviews the different types of heterogeneity that might exist among trials that are involved in the overview: study design, randomization procedure, treatment evaluation, statistical evaluation, and data maturity. In order to overcome these various types of heterogeneity and to compare like with like, the treatment comparison should be stratified a posteriori by question (i.e., type of castration or type of anti-androgen studied) and by study. In this way, one may draw valid conclusions. Of course, those trials with a larger number of patients and a longer follow-up will contribute more to the overview's results.

Androgen Antagonists↗
PubMed1993

Orchidectomy versus goserelin plus flutamide in patients with metastatic prostate cancer (EORTC 30853). European Organization for Research and Treatment of Cancer--Genitourinary Group.

A total of 327 patients with metastatic prostate cancer were randomized to receive bilateral orchiectomy or treatment with Zoladex and flutamide. The trial aimed to evaluate subjective and objective time to progression, survival, and incidence and duration of response. Strict quality control and evaluation by independent ad hoc committees were organized. Progression was assessed for each of 13 parameters. The time to subjective and objective progression was in favor of the combination treatment, with statistical significances of P = 0.009 and P = 0.008, respectively. This delay in objective progression resulted in increased survival in favor of the combination treatment for death by cancer (P = 0.02) or overall survival (P = 0.05). Survival differences were more marked in the patients with better prognostic factors. The clinical significance of these differences for the individual patient requires detailed assessment.

Adult↗
PubMed1993

Prostate cancer. Primary hormonal treatment.

BACKGROUND: No other treatment matches the 40-60% objective response and up to 80% subjective responses for primary hormonal therapy in patients with symptomatic disease. This makes primary hormonal treatment first-line therapy metastatic prostate cancer. RESULTS: The treatment outcome is determined by the initial and intermittent prognostic factors. In the multihormonal environment, several endocrine treatments have shown competing levels of response. Maximal androgen blockade has emerged as the best treatment to achieve a response and even has increased survival modestly. Monotherapy with nonsteroidal antiandrogens plays a role in patients trying to preserve their potency. CONCLUSIONS: Pilot treatment adjusted to the medical needs and social preferences of the patient is appropriate and allows a tailored approach to the individual patient.

Combined Modality Therapy↗
PubMed1993

Ketoconazole and liarozole in the treatment of advanced prostatic cancer.

BACKGROUND: Ketoconazole, an imidazole derivative, is an orally active antifungal agent. In high doses (400 mg three times a day), it inhibits the biosynthesis of testicular and adrenal androgens and may therefore be useful for the treatment of hormone dependent diseases such as advanced prostatic cancer. Similarly, a new imidazole derivative, liarozole, was recently found to interfere with testicular and adrenal steroid biosynthesis in animals and healthy volunteers. METHODS: The therapeutic and endocrine effects of ketoconazole and liarozole in patients with disseminated prostatic cancer are discussed, including data from the literature and personal experience. RESULTS: Using high-dose ketoconazole, medical castration with the expected clinical response was achieved easily in previously untreated patients in all clinical series (personal data include seven patients). In patients with prostatic cancer who had relapses after castration, few objective remissions were achieved. By contrast, long-lasting subjective remissions, especially pain relief, were seen in more than half of the patients (personal data include 20 patients). Gastrointestinal intolerance, which was the main side effect, severely limits the routine use of the drug. Recently, the authors studied the effect of liarozole on adrenal steroid production in castrated patients whose disease was progressive after first-line treatment. Unlike ketoconazole therapy, adrenal androgen and cortisol levels were not modified. A Phase I-II trial was then done in 44 patients with metastatic prostatic cancer in clinical relapse. In patients with measurable disease, objective responses, including tumoral volume reduction, occurred in approximatively 30%. A prostate specific antigen reduction of 50% or more was noted in approximatively 50% of patients. Pain relief occurred in most patients. Mucocutaneous side effects were observed in most patients--dryness of the skin and onychomalacia. Raised tissue retinoic acid levels suggested a possible pathway by which this drug might exert its cytotoxic effects. CONCLUSIONS: Ketoconazole in high doses is effective in first-line and second-line therapy for advanced prostatic cancer, but gastrointestinal side effects limit its routine use. Liarozole is a new imidazole that is also effective in second-line therapy for prostatic cancer and has fewer side effects. Unlike ketoconazole, its effect is not mediated by inhibition of steroid biosynthesis.

Aged↗
PubMed1993

Quality of life in patients with prostatic cancer. A feasibility study. The Members of Quality of Life Committee of the EORTC Genitourinary Group.

BACKGROUND: In recent years, there has been a growing recognition of the need to include parameters representing the patients' view of their conditions that, therefore, are more subjective in nature. METHODS: As a first effort to introduce quality-of-life (QOL) assessment in prostatic cancer clinical trials, the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group, in cooperation with the EORTC QOL Group, activated Protocol 30853 (orchiectomy versus goserelin acetate and flutamide in previously untreated patients with Stage M+ disease. Study Coordinator: Louis Denis). The use of patient-administered QOL questionnaires was optional, and of 327 patients, only 22% underwent pretreatment assessments. RESULTS: Psychologic distress, fatigue, social and family life, and pain are the most important to the patient on a subjective basis, and these were confirmed in relation to objective parameters. There was a discrepancy between the doctors' evaluations and the patients' opinions about subjective morbidity, namely, in regard to sexual status and pain. CONCLUSIONS: This EORTC trial revealed the reluctance of clinicians to do QOL research, partly related to feasibility problems and partly to the doctors' doubts about the value of such efforts. QOL assessment should become a mandatory part of clinical trials in prostatic cancer.

Activities of Daily Living↗