Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer.

A phase I study was performed of CGS 20267, an oral nonsteroidal, highly potent, and selective aromatase inhibitor, in 21 postmenopausal patients with advanced breast cancer. The patients were recruited in 3 successive groups of 7, receiving 0.1, 0.5, and 2.5 mg p.o./day, respectively. All patients had received at least one prior endocrine treatment (range, 1-4), and six patients had received prior chemotherapy. The treatment was very well tolerated, and no toxicity was seen at any of the three doses. There was a statistically significant suppression of estradiol (E2) and estrone (E1) levels by 74% and 79% from baseline levels, respectively (P < 0.0001). Suppression occurred in all three patient groups, with many patients having serum concentrations of estradiol and estrone, which were below the limit of detection of the assays (3 and 10 pM, respectively), which corresponds to a maximum measurable estrogen suppression of 86%. CGS 20267 had no significant effect on serum levels of follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, cortisol, 17 alpha-hydroxyprogesterone, androstenedione, and aldosterone. Seven (33%, 95% confidence interval, 15-57%) of the 21 patients have responded to treatment (one complete remission, 6 partial remissions according to criteria of the Union Internationale contre le Cancer), and 6 are still responding to CGS 20267 (duration of response; 4+, 6+, 6+, 9+, 9, 12+, and 12+ months). Five have had stable disease for more than 3 months, and 9 had progressive disease. These results suggest that CGS 20267 is a very potent and specific aromatase inhibitor, and phase II studies are now required to confirm its clinical efficacy.

Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.

PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer.

Thirteen postmenopausal women with advanced breast cancer were enrolled in an open randomized Phase I trial of a new p.o. active aromatase inhibitor, CGS 20267 (letrozole). The primary aim of the trial was to assess the impact of two doses of letrozole (0.5 and 2. 5 mg/day) on the peripheral aromatization of androstenedione to estrone. An in vivo isotopic technique was used to measure peripheral aromatization in each patient before treatment. The patients were then randomly assigned to one of the two doses, and measurements of aromatization were repeated after 6 weeks. At 0.5 mg and 2.5 mg/day, letrozole inhibited aromatization by 98.4% (97.3 to >99.1) and >98.9% (98.5 to >99.1; geometric means and ranges), respectively. Plasma estrogen levels were also measured before and during treatment. At the dose of 0.5 mg/day estrone and estradiol levels fell by 82.0% and 84.1% (geometric means), respectively. At the dose of 2.5 mg/ day, the estrogens fell by 80.8% and 68.1%, respectively. There were no significant differences between the doses in aromatase inhibition. No formal statistical analysis was performed on the estrogen data. Letrozole is therefore a highly effective inhibitor of aromatase, causing near complete inhibition of the enzyme in peripheral tissues at the doses investigated. The falls in estrogen levels were greater than those seen with earlier generation aromatase inhibitors.

Open dose-finding study of a new potent and selective nonsteroidal aromatase inhibitor, CGS 20 267, in healthy male subjects.

The aim of this open, dose-finding study was to evaluate the effects of single dose CGS 20 267, a new oral nonsteroidal aromatase inhibitor, on the inhibition of estrogen production and also on the production of adrenal and testicular steroids in healthy male subjects. Nine dose levels ranging from 0.02-30 mg and placebo were tested, each dose being given to 3 subjects only. A total of 18 subjects were included; 12 of them received 2 single administration, the remaining 6 were exposed only once to one of the 2 highest dose levels. A reduction in serum estrogen levels when compared to baseline was already observed after 2 h, reaching maximum suppression between 10 and 48 h after administration. After 24 h, a suppression of estrone levels by 60-85% from baseline was achieved with all tested doses. A reduction in estradiol levels by about 30% from baseline was observed at the lowest dose (0.02 mg). This reduction was further enhanced dose dependently to a maximum of about 90% from baseline at 24 h after administration of the highest dose (30 mg). With the higher doses (10 and 30 mg), estrogen suppression was maintained up to 3 days. A dose-dependent increase of testosterone, LH, and FSH was observed and was most pronounced in the 10- and 30-mg dose groups, which can be considered as a consequence of the long-lasting aromatase inhibition achieved with these high doses. No effect on serum cortisol and aldosterone levels was observed up to the highest dose. No clinically relevant changes were observed in blood chemistry and hematology tests. The systemic and subjective tolerability of CGS 20 267 was good at all doses. This study has shown that CGS 20 267 is a well tolerated, potent, selective, and long-acting inhibitor of the aromatase enzyme after single administration.

Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women.

We have performed a phase I study of the effect of a single dose of CGS 20267, an oral nonsteroidal aromatase inhibitor, in 12 healthy volunteer postmenopausal women. Each subject received 2 single doses of CGS 20267 (0.1, 0.5, or 2.5 mg) or placebo separated by a washout period of at least 6 weeks. There was statistically significant suppression of serum estrone and estradiol at all three doses of CGS 20267 tested. Serum estrone and estradiol concentrations were maximally suppressed by 76% and 79% from baseline levels, respectively. Urinary excretion of estrone and estradiol was also suppressed, although this did not reach statistical significance. Serum concentrations of aldosterone, cortisol, 17 alpha-hydroxyprogesterone, androstenedione, testosterone, FSH, LH, and TSH were unaffected by CGS 20267. The drug was well tolerated, with no significant side-effects. This study has shown CGS 20267 to be a potent and specific aromatase inhibitor, and further studies are now needed to assess its clinical efficacy.

The effects of fadrozole hydrochloride on aldosterone secretion in healthy male subjects.

The aim of this double blind placebo-controlled cross-over study was to evaluate the effects of fadrozole, a new oral nonsteroidal aromatase inhibitor, on basal and stimulated cortisol and aldosterone secretion at a daily dosage of 4 mg given for 14 days to eight healthy men. After 2 weeks of treatment, fadrozole, compared with placebo, effectively suppressed plasma estrogen levels (P less than 0.05 at 0800 h), but did not affect glucocorticoid secretion either under basal conditions or after stimulation with ACTH. Basal plasma aldosterone levels were not significantly different with fadrozole treatment compared to those after placebo treatment. However, compared with pretreatment values, basal aldosterone secretion appeared impaired (P less than 0.05). A statistically significant blunting of the responses of plasma aldosterone to ACTH (P less than 0.01) and upright posture (P less than 0.01) after fadrozole compared with placebo treatment further indicated that fadrozole impaired basal aldosterone secretion. This attenuation of aldosterone secretion was accompanied by a rise of PRA in the basal condition (P = 0.05) and after stimulation by 40 mg furosemide (P less than 0.01) and upright posture (P less than 0.01). An increase in deoxycorticosterone was observed after fadrozole treatment compared with pretreatment values (P less than 0.01) and after stimulation with ACTH compared with placebo (P less than 0.05). This study confirms that fadrozole given in daily doses of 4 mg is an effective aromatase inhibitor which does not affect glucocorticoid secretion. However, this dose may induce an impairment of aldosterone secretion which is modest and revealed mainly under specific stimulatory conditions, and does not lead to clinical symptoms of hemodynamic dysregulation or a relevant disturbance of serum electrolytes.

Endocrine changes with the aromatase inhibitor fadrozole hydrochloride in breast cancer.

Fadrozole hydrochloride is a potent aromatase inhibitor with proven clinical effectiveness. However, its optimal dose and its effects on serum aldosterone levels/electrolyte balance have been disputed. To resolve these issues, a double-blind randomised endocrine study of three doses of fadrozole hydrochloride [0.5 mg twice daily (bd); 1.0 mg bd; 2.0 mg bd] was conducted in 80 (68 evaluable) postmenopausal patients with advanced breast cancer over a period of 3 months. There were substantial falls in the serum levels of oestradiol, oestrone and oestrone sulphate. For oestrone only, there was a significant effect of dose (on-treatment means: 0.5 mg, 38.0 pmol/l; 1.0 mg, 25.0 pmol/l; 2.0 mg, 23.9 pmol/l). All oestrogens showed a similar pattern in relation to time, with the 3-month mean being higher than those at 1 and 2 months, and this was significant for oestradiol (P = 0.012). There was an indication that complete suppression of oestradiol and oestrone was not maintained throughout the 12-h dosing period, but the data and its interpretation are complicated by a minor diurnal rhythm in these parameters. There were significant increases in 17-hydroxyprogesterone and androstenedione which may be due to a block of 11 beta-hydroxylase. There was a statistically non-significant fall in aldosterone levels (P = 0.06) during treatment (median pretreatment, 446 pmol/l; median decrease, 125 pmol/l). However, the concurrent significant fall in the plasma sodium: potassium ratio indicated that changes in aldosterone secretion did occur. None of these effects on adrenal pathways was of a degree which is likely to have clinically relevant consequences. It is concluded that fadrozole hydrochloride achieves near maximal suppression of oestrogens at 1 mg bd, and that its effects on aldosterone synthesis are unlikely to be of clinical significance.

Influence of caloric intake on the respiratory mode during mandatory minute volume ventilation.

Mandatory minute volume ventilation has been proposed as a method for weaning patients from ventilators. The purpose of this study was to delineate the influence of caloric intake on spontaneous ventilation in patients receiving mandatory minute volume ventilation. While the value of such ventilation remained unchanged, eight patients were studied at the following three different levels of daily caloric intake: (1) level A, mean of 223 kcal/sq m; (2) level B, mean of 1,380 kcal/sq m; and (3) level C, mean of 2,100 kcal/sq m. We performed gas exchange measurements and a 24-hour recording of ventilation with a monitoring system providing distinction between spontaneous and mechanical cycles. We found that the ventilatory mode was markedly dependent upon the nutritional intake; the percentage of spontaneous ventilation over 24 hours increased from 11 +/- 7 percent (+/- SE) during diet A to 50 +/- 9 percent during diet B and 79 +/- 8 percent during diet C. This increment paralleled the increase in production of carbon dioxide with caloric intake. We suggest therefore that the patient's ability to breathe spontaneously when receiving mandatory minute volume ventilation should be interpreted according to caloric intake.

Clinical use of aromatase inhibitors in the treatment of advanced breast cancer.

The aim of endocrine therapy is to reduce the estrogenic stimulus for tumour growth. After failure of tamoxifen--the standard "first-line" hormonotherapy for advanced breast cancer (ABC)--the most frequently prescribed endocrine therapies are progestins and aromatase inhibitors (AIs) ("second-line" hormonotherapy). Estrogen deprivation through AIs provides effective treatment of hormone-dependent ABC in postmenopausal (PMP) women. Over the past few years, the goals of our research programme were to develop more potent, more selective and better tolerated AIs than our first AI, aminoglutethimide (AG). Lentaron (4-hydroxyandrostenedione, formestane), a highly selective steroidal compound was the first of the new AIs to be used in clinical trials. It is a substrate analogue, administered as an i.m. injection every 2 weeks. It is effective in the treatment of ABC with an objective response rate (ORR) similar to tamoxifen and megestrol acetate (MA) and is generally well tolerated; rare instances of injection site reactions have been reported. Afema (fadrozole HCl), a non-steroidal AI is active orally, and effectively suppresses estrogen levels in PMP women, but it is not completely selective for aromatase when administered at higher than therapeutic doses. At the therapeutic dose of 1 mg twice a day it has an anti-tumour efficacy similar to MA, a good tolerability and no clinically relevant effects on other hormones of the endocrine system. Letrozole is the fourth of our AIs in clinical development. It is a non-steroidal, achiral, orally active, potent and highly selective competitive AI. Clinical endocrine studies have shown that the dose of 0.5 mg a day is the lowest dose achieving maximum estrogen suppression. Over a wide dose range, a lack of clinically relevant effects on other hormones of the endocrine system has confirmed its high selectivity. In four phase Ib/IIa studies in PMP patients with ABC who failed previous therapy, letrozole produced ORRs of 9, 31, 33 and 36%. One phase IIb/III study has been completed and two others are ongoing, comparing two doses of letrozole with MA or AG to confirm the anti-tumour efficacy of letrozole in the treatment of ABC in PMP women after treatment with anti-estrogens. Preliminary results from the completed trial show that letrozole 2.5 mg is superior to 0.5 mg in terms of ORR, time to progression and time to treatment failure, and is superior to the standard dose of MA in terms of ORR and tolerability. Therefore letrozole 2.5 mg can be recommended as a first choice for the treatment of PMP patients with hormone receptor-positive or unknown ABC after anti-estrogen therapy.

Inhibition of estrogen biosynthesis and its consequences on gonadotrophin secretion in the male.

Of the gonadal steroids in the male, testosterone is the most important regulator of gonadotrophin secretion. However, whether testosterone affects gonadotrophin secretion directly or whether it must first be aromatized to estrogens is controversial. We have reported extensively on the endocrine and anti-tumor effects of the non-steroidal aromatase inhibitors CGS 16949A and CGS 20267 in adult female rats. In these animals, both inhibitors potently and selectively inhibit estrogen biosynthesis. Thus these agents can be effectively used in studying estrogen-dependent processes. CGS 16949A was administered for 14 days to adult male rats, over a dose range which in females suppresses estradiol and elevates LH. In male rats a suppression of estradiol was seen, however, there was no significant effect on either serum LH or on the weights of androgen-dependent organs. CGS 16949A, when administered to healthy men at a dose of 1 mg b.i.d. for 10 days, causes a significant fall in plasma estradiol and significant elevations of plasma FSH and testosterone. Dose-dependent suppression of serum estradiol and an increase in serum testosterone and LH are seen after administration of single oral doses of CGS 20267. These results indicate that in the male rat, inhibition of aromatization of testosterone to estrogens does not influence gonadotrophin secretion whereas in men the negative feedback exerted by testosterone on gonadotrophin secretion is dependent on the aromatization of testosterone to estrogens.

The role of drug-induced illness in admissions to an intensive care unit.

All patients admitted during a 33-month period to a multidisciplinary intensive care unit were prospectively studied in order to determine the incidence and severity of drug-induced illness leading to the admission. The role of underlying diseases was assessed and the avoidability of drug-induced illness considered. Out of 1651 patients, 97 (5.88%) were admitted because of drug-induced illness; 74 of these had serious underlying diseases. 13 (13.4%) of the 97 patients died, but underlying diseases accounted for 4 of the 13 fatalities. In nearly half of the cases, the drug-induced illness appeared potentially avoidable.

Computed tomography and post-laparotomy intra-abdominal abscesses.

Thirty-one patients were prospectively studied and had abdominal computed tomography for post laparotomy sepsis. Computed tomography is of particular interest in seriously ill post-operative patients, 15 of our patients were on ventilators, and it enabled diagnosis and localization of abscesses in 15 patients. Drainage could therefore be achieved via a limited surgical approach, and extensive laparotomy was avoided. Of 16 patients without abscess, the abdominal computed tomogram was negative in 14 cases and there were two false positives. The overall accuracy was 0.94 with a sensitivity of 1 and a specificity of 0.88. The ability to screen the whole abdomen and exactly localize the lesion are the advantages of this non-invasive method.

Decreased plasma epinephrine concentrations after glucose ingestion in humans.

Plasma levels of norepinephrine (NE), epinephrine (E), immunoreactive insulin (IRI), and glucose were measured in six healthy volunteers after glucose consumption and in six volunteers after a water solution. Ingestion of the glucose (100 g) solution significantly decreased E levels from 46.7 +/- 8.0 to 20.8 +/- 1.9 pg/mL (P less than 0.01). Three hours after the glucose ingestion, plasma E levels nearly returned to basal values. Plasma IRI and glucose levels peaked at 45 minutes after glucose consumption (P less than 0.01), then declined toward basal values. Plasma NE levels were unaffected by glucose consumption. There were no changes in glucose, IRI, NE, or E levels in the control group. These results suggest that E behaves as a counter-regulatory hormone to insulin under stimulation by glucose.

[New developments in the hormonal treatment of breast cancer in postmenopausal women]. / Nouveaux développements dans l'hormonothérapie du cancer du sein chez la femme ménopausée.

Nowadays the role of the hormonotherapy in the treatment of breast cancer in postmenopausal women is well established. The benefit of tamoxifen is demonstrated in the adjuvant setting as well as in the treatment of advanced breast cancer. After tamoxifen failure the hormonosensitive patients can be offered a second and a third hormonal treatment. The developments of new hormonotherapies recently or shortly put at the disposal of oncologists, such as new antiestrogens or selective estrogen receptors modulators (SERM), new steroidal and nonsteroidal aromatase inhibitors and antiprogestins are reviewed as well as the recent data on the use of tamoxifen in the primary prevention of breast cancer. The principal characteristics and the potential therapeutic uses of these agents are reviewed in the treatment and prevention of breast cancer in postmenopausal patients.

[Suppurating splenic infarction originating from endocarditis]. / Infarctus spléniques suppurés d'origine endocarditique.

Three cases of splenic infarction complicated by abscess formation during bacterial endocarditis are reported. In all three cases there were associated clinical abdominal signs and, in one case, there was persistently positive hemocultures. The diagnosis was made by CAT scanning. The three patients underwent splenectomy and one patient also underwent valve replacement the same day. The methods of early diagnosis of splenic complications during endocarditis and the indications of splenectomy are discussed. Ultrasonography and abdominal CAT scanning are the most sensitive diagnostic methods for splenic lesions. As splenic rupture is associated with a high mortality and this complication may occur at any time during infarction complicated by abscess formation, early splenectomy is justified when abdominal clinical signs are elicited associated with a persistent, infectious syndrome with or without positive blood cultures, under appropriate antibiotic therapy. Splenectomy should also be considered if valve replacement is carried out in the same circumstances to avoid infection of the prosthesis.

[Industrial drug-surveillance. Spontaneous notification: data collection, survey]. / Pharmacovigilance industrielle. Notification spontanée: recueil, enquête.

The importance of post-marketing drug surveillance has often been stressed. To detect new undesirable side-effects it seems more appropriate to improve spontaneous reporting of such effects. The main stages of spontaneous reporting are listed, with detailed information on his first and second stages: data recording and validation.

[Prospective evaluation of the complications of anticoagulants in an intensive care unit]. / Evaluation prospective des accidents des anticoagulants en unité de réanimation.

A prospective study was undertaken in a multidisciplinary intensive care unit to determine the proportion of complications due to anticoagulant therapy, to evaluate their severity and to estimate what proportion was potentially avoidable. Among 1911 hospitalized patients over a 3 year period, 30 patients had a complication of anticoagulant therapy (1,57 p. 100). The causality was definite in 14 cases, probable in 14 and possible in 2 cases. Nineteen p. 100 were hemorrhagic complications. These iatrogenic illnesses were fatal in 5 cases, life-threatening in 6, moderate in 15 and minor in 4 cases. Potentially avoidable complications accounted for 60 p. 100 of the cases and were due to biological overdosage or interaction between drugs. Our results indicate that some complications of anticoagulant therapy could be reduced or eliminated by medical education and increased information.

[Acute adult respiratory distress syndrome after lymphography]. / Syndrome de détresse respiratoire aiguë de l'adulte après lymphographie.

Pulmonary complications of lymphography are usually described as radiological infiltrates without clinical symptoms. However, a case is here reported of an adult respiratory distress syndrome occurring after lymphography in a 60 year old female lymphoma patient. Pulmonary oedema developed within 48 h; haemodynamic study showed a normal capillary wedge pressure. The patient died from intractable low cardiac output within 24 h. Post-mortem examination showed pulmonary lymphocytic infiltration and multiple fat emboli. The lack of lymphatic drainage was probably responsible for the intravascular passage of lipid-soluble contrast medium, this giving endothelial lesions. In such patients with preexisting lung disease or pulmonary involvement in haematological disease, lymphography has to be considered carefully.

[Hyperthermia during parenteral nutrition]. / Hyperthermie au cours de la nutrition parentérale.

In a woman with caustic burn of the oesophagus total parenteral nutrition (3000 calories, 16 g nitrogen daily) resulted in a rise in body temperature from 37 to 39 degrees C. Temperature returned to normal when nutrition was discontinued to rise again when it was resumed. No infection or other cause of fever was detected. This case suggests that high calorie and nitrogen parenteral nutrition may induce hyperthermia, the possible mechanisms of which are discussed.

[Increase in partial arterial carbon dioxide pressure due to parenteral nutrition during artificial ventilation]. / Augmentation de la pression partielle artérielle en gaz carbonique due à la nutrition entérale au cours de la ventilation artificielle.

The influence of increased enteral caloric intakes on respiratory gas exchanges was evaluated in 6 patients (5 men, 1 woman; mean-age: 54 years) in steady state and requiring continuous ventilatory support. Oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory quotient (R), determined using an open circuit indirect calorimetric method, and arterial blood gases were measured on two consecutive days while ventilation conditions were unchanged. On the first day, the patients received a water diet only and on the following day an enteral caloric load (1491 +/- 65 Kcal/m2/24 h). The results showed a significant increase in VO2 (p less than 0.05) and R (p less than 0.001) and a rise in VCO2 from 106 +/- 4 to 139 +/- 9 ml/mn/m2 (p less than 0.01). The rise in VCO2 induced an increase of arterial carbon dioxide tension (PaCO2) from 26.3 +/- 1.6 to 34.4 +/- 2.4 mmHg (p less than 0.001). This study showed that because of the constancy of alveolar ventilation, the enteral nutrition-related increase of VCO2 is responsible for a PaCO2 increase and emphasized the need for adjusting artificial ventilation to any change in caloric intake in patients supported with mechanical ventilation.