A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer.

OBJECTIVES: To evaluate the levels of testosterone and other hormones in men with prostate cancer treated with abarelix versus leuprolide acetate. METHODS: Patients (n = 269) were randomized to receive open-label abarelix 100 mg or leuprolide acetate 7.5 mg by intramuscular injection. The results of the first 84 days of the study are reported. The primary efficacy endpoints included avoidance of testosterone surge, castration on day 8, and achievement and maintenance of castration from days 29 through 85. The secondary endpoints included castration on days 2, 4, and 15; a reduction in prostate-specific antigen level; and measurements of other hormones. Patients were monitored for clinical adverse events and laboratory abnormalities. RESULTS: No men in the abarelix group and 82% of men in the leuprolide acetate group experienced a testosterone surge (P <0.001). Abarelix caused rapid medical castration: 24% of men 1 day after treatment and 78% after 7 days compared with 0% of men treated with leuprolide acetate on either day. A comparable percentage of men achieved and maintained castration between days 29 and 85 in each group. Prostate-specific antigen had a statistically significant decrease for the first month in patients treated with abarelix. Dihydrotestosterone, luteinizing hormone, prostate-specific antigen, and follicle-stimulating hormone showed similar rapid reductions without an initial increase. The overall occurrence of adverse events was similar across the treatment groups, and most were sequelae of comorbid disorders. CONCLUSIONS: Treatment with abarelix produced a higher percentage of patients who avoided a testosterone surge and had a more rapid time to testosterone suppression with a higher rate of medical castration 1 day after treatment and greater reductions in testosterone, luteinizing hormone, follicle-stimulating hormone, and dihydrotestosterone during the first 2 weeks of treatment compared with leuprolide acetate. The achievement and maintenance of castration was comparable between the two groups.

Filgrastim in patients with pneumonia and severe sepsis or septic shock.

STUDY OBJECTIVES: Evaluate the safety of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) administration, combined with standard therapy, in patients with pneumonia and either septic shock or severe sepsis who were receiving mechanical ventilation. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: ICU, multicenter. PATIENTS: Eighteen patients with pneumonia and hypotension, or in the absence of shock, two or more end-organ dysfunctions, were enrolled and treated. Baseline acute physiology and chronic health evaluation II scores and median age for the filgrastim (n = 12) and placebo (n = 6) groups were 25.0 and 49.5 years and 31.5 and 56.5 years, respectively. INTERVENTION: Filgrastim (300 microg) or placebo was administered IV daily for up to 5 days. MEASUREMENTS AND RESULTS: Study end points included safety; biological response, including endogenous cytokine levels, endotoxin levels, and neutrophil counts; and mortality. Cytokine and endotoxin levels were highly variable in both groups. By day 29, 3 of 12 filgrastim-treated patients and 4 of 6 placebo-treated patients had died. There were no differences in types and occurrences of adverse events, including ARDS, or in outcome between the two groups. Three of four placebo-treated patients had persistent bacterial growth on bronchoscopy repeated after 48 h compared with 2 of 10 filgrastim-treated patients. CONCLUSION: Filgrastim appeared to be well tolerated in this population of patients with pneumonia and severe sepsis or septic shock. Larger studies to determine the benefit of filgrastim in patients with pneumonia and sepsis or organ dysfunction are warranted.

A randomized controlled trial of filgrastim for the treatment of hospitalized patients with multilobar pneumonia.

This study assessed the safety and efficacy of filgrastim (r-metHuG-CSF [recombinant human methionine granulocyte colony-stimulating factor]), when combined with intravenous (IV) antibiotics, in the treatment of hospitalized adult patients with multilobar community-acquired pneumonia (CAP). Four hundred eighty patients were randomized to receive placebo (n=243) or filgrastim 300 microg/day (n=237), in addition to standard therapy. Treatment with study drug was continued for 10 days, until the peak white blood cell (WBC) count reached 75x109/L, until discharge from the hospital, until death, or until IV antibiotics were discontinued. Study-related observations continued through day 29. Filgrastim increased WBC counts (baseline median, 13.3x109/L; median peak, 43. 8x109/L). The 2 treatment groups were not statistically different with respect to the study end points; however, there was a trend toward reduction of mortality in patients with pneumococcal bacteremia. Although further studies will be required to validate this observation, filgrastim was safe and well tolerated when administered to patients with multilobar CAP.

Randomized, placebo-controlled, double-blind, multicenter trial of efficacy and safety of granulocyte colony-stimulating factor in liver transplant recipients.

BACKGROUND: Infection and rejection are two common complications after liver transplants. In a preliminary study, administration of granulocyte colony-stimulating factor (G-CSF) to liver transplant recipients was associated with a decrease in sepsis episodes, sepsis-related deaths, and rejection compared with a historical control group of patients. The purpose of this study was to evaluate further the efficacy of G-CSF in liver transplant patients in a randomized, placebo-controlled, double-blind, multicenter trial. METHODS: Adult patients with a United Network Organ Sharing classification of 1 or 2 were randomized to receive a placebo, 100 microg/day of G-CSF or 300 microg/day of G-CSF. The study drug was started preoperatively and then continued after the transplant for a maximum of 21 days. Patients were evaluated for microbiologically-documented infection, biopsy-proven rejection, number of treatments for rejection, length of stay in the intensive care unit and hospital, graft survival, death, and adverse events. RESULTS: During the first 30 days after the transplant, the median peak white blood cell count was 16.5x10(9)/L, 34.6x10(9)L, and 54.8x10(9)/L for the placebo, low-dose G-CSF, and high-dose G-CSF patients, respectively. The incidence of infection was 30% in G-CSF patients (34 of 114 patients) and 34% in placebo patients (20 of 58 patients). Except for more nosocomial pneumonias in the G-CSF patients (7 in 114 patients vs. 0 in 58 patients, P=0.056), the types of infections and causative organisms were also similar in both treatment groups. Although the number of treatments for clinically suspected or proven rejection was similar in the G-CSF and placebo patients, biopsy-proven rejection occurred more often in G-CSF patients (34 of 114 patients or 30%) than placebo patients (11 of 58 patients or 19%) (P=0.093). There were no cases of graft loss caused by rejection. G-CSF had no effect on length of stay in the intensive-care unit or hospital. There were 22 G-CSF patients (18%) and 10 placebo patients (15%) who died within 120 days after the transplant. No serious adverse events were attributed to G-CSF. CONCLUSION: Despite producing substantial increases in the white blood cell count after the transplant, G-CSF had no beneficial effects on infection, rejection, or survival in this study. Biopsy-proven rejection and nosocomial pneumonias were more common in patients treated with G-CSF compared with those taking the placebo. No serious adverse events were attributed to G-CSF.

A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group.

Because of the critical role of neutrophils in host defenses, it was hypothesized that stimulation of neutrophil production and function with Filgrastim would improve the outcome of hospitalized patients with community-acquired pneumonia. To test this hypothesis, a randomized, placebo-controlled, multicenter trial of Filgrastim (300 micrograms/day up to 10 days) as an adjunct to antibiotics was conducted for these patients. Outcome measures included time to resolution of morbidity (TRM, a composite measure of temperature, respiratory rate, blood oxygenation, and chest radiograph), 28-day mortality, length of stay, and adverse events. Filgrastim increased blood neutrophils 3-fold, but TRM, mortality, and length of hospitalization were not affected. Treatment, however, accelerated radiologic improvement and appeared to reduce serious complications (e.g., empyema, adult respiratory distress syndrome, and disseminated intravascular coagulation). Filgrastim administration was safe and well tolerated in these patients. Additional trials are needed to establish the value of this approach to treatment of infectious diseases.

Time to resolution of morbidity: an endpoint for assessing the clinical cure of community-acquired pneumonia.

Clinical trials of new therapeutics for community-acquired pneumonia (CAP) have typically used a subjective endpoint of clinical response. However, as this endpoint is not quantitative, it is subject to observer bias and renders the conduct of multicenter trials difficult. For the purposes of conducting a clinical trial of filgrastim, as an adjunct to antibiotics for the treatment of CAP, a set of clinical criteria were developed prospectively to determine the time when a clinical cure was achieved, based on respiratory rate, temperature, oxygenation and roentgenographic findings, which was termed the time to resolution of morbidity (TRM). The TRM was evaluated on the first 100 patients entered in this clinical trial. As no clear reference standard exists, the predictive value for the duration of parenteral antibiotics (AB) and the length of hospital stay (LOS) was compared with that provided by a widely used classification system for severity of disease, APACHE II. The TRM was found to correlate significantly better with AB or LOS than APACHE II (P < 0.001). Furthermore, TRM offers the benefit over the endpoints of LOS and AB of being specifically designed to measure the patient's response to therapy, and, in fact, may aid physicians in determining the duration of parenteral antibiotic therapy. Hence, TRM is relevant to the clinician and is a useful tool to ensure uniformity in the assessment of the response to a new therapeutic in a multicenter clinical trial.

Monocyte monolayer assay as a predictor of severity of hemolytic disease of the fetus and newborn.

The monocyte monolayer assay (MMA), an in vitro model of in vivo antibody-mediated red blood cell destruction, was previously reported to predict the severity of hemolytic disease of the fetus and newborn accurately when only Rh antibodies and antigen-positive babies were studied. We studied 33 women whose serum contained antibodies with the potential to cause erythroblastosis fetalis; 7 of the 33 women had antibodies other than Rh. None of the babies of the ten women who had consistently negative test results required intrauterine or neonatal transfusions. False-positive MMA results were sometimes found when the fetus was antigen negative. Although the predictive value of a negative MMA was 100%, the efficiency of the MMA was no better than that of the antibody titer. Because of the lack of advantage of the MMA as well as the time and expense it requires, we cannot recommend the general clinical application of this test at this time.

Could the fasting plasma glucose assay be used to screen for gestational diabetes?

The fasting plasma glucose assay was compared with the one-hour post-glucose test as a screening test for identification of gestational diabetes. Of 4,561 consecutive patients screened with a 50-g glucose test, 968 (21.2%) had results > or = 135 mg/dL; 141 (14.6%, or 3.1% of the total) were found to have diabetes. In the 968 patients, the area under the fasting plasma glucose receiver operating characteristic curve was greater than that under the glucose screening test curve, indicating greater discriminatory value of the former test. Of the 116 patients who had sequential glucose screening tests and fasting plasma glucose assays performed twice during pregnancy, a significant correlation was found for fasting plasma glucose values, but not for glucose screening test values. We conclude that the fasting plasma glucose assay may perform better than the one-hour post-glucose test as a screening test for gestational diabetes. Based on these data, a population-based prospective study seems justified.

A randomized trial of three methods of obtaining Papanicolaou smears.

The relationship between technique of obtaining Papanicolaou smears, presence of endocervical cells, and rate of cervical neoplasia was studied by comparing an endocervical and ectocervical nylon brush (Bayne brush), Ayre spatula plus endocervical brush, and spatula plus cotton-tipped swab in a randomized, prospective trial involving 11,061 patients. Eligible patients had a cervix and were not pregnant. Clinic records of patients with abnormal cytology were reviewed to determine the pathologic diagnosis. Whether pathology was defined as including condyloma, dysplasia, and cancer; dysplasia and cancer; moderate dysplasia, severe dysplasia, and cancer; or just severe dysplasia and cancer, no significant difference was found in the rates of pathology between the three techniques. Endocervical cells were identified in 89.5% of smears obtained with the Bayne brush, in 91.5% with the spatula plus endocervical brush, and in 71.1% with the spatula plus cotton-tipped swab (P less than .001). Among smears obtained with the spatula plus swab, the rate of any pathology was higher in smears that contained endocervical cells than in smears in which endocervical cells were absent (2.0 versus 0.6%; P = .009). After correction for the influence of age, there remained predictive value with the presence of endocervical cells. Once corrected for the influence of age, the rate of pathology and abnormal cytology in smears obtained with the spatula plus brush or the Bayne brush was not dependent upon the presence of endocervical cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Presentation of cervical cancer.

To determine how patients with invasive cervical cancer present and whether presentation affects disease-free survival (DFS), a review of 81 patients treated for cervical cancer by the Division of Gynecologic Oncology and Pelvic Surgery at the Southern California Permanente Medical Group between January 1, 1986, and December 31, 1986, was performed. Fifty-six percent of patients presented with abnormal vaginal bleeding, twenty-eight percent presented with abnormal Papanicolaou (Pap) smears, nine percent presented with pain, four percent presented with vaginal discharge, and four percent presented with other symptoms. Follow-up was 24 to 41 months. Patients presenting with abnormal Pap smears had DFS of 96%. Those presenting with abnormal vaginal bleeding had DFS of 51% and those presenting with pain had DFS of 29%. Presentation strongly influences DFS (chi 2 = 16.8, P less than 0.001). Of women presenting with abnormal Pap smears, 87% were Stage I and 13% were Stage II. Of women presenting with other than abnormal Pap smears, 40% were Stage I, 34% were Stage II, and 26% were Stage III or IV. Presentation with abnormal Pap smear and stage are significantly related (chi 2 = 14.8, P less than 0.001). Of women presenting with abnormal Pap smears, 89% had cancers 0 to 2 cm, 5% had cancers 2.1 to 4 cm, and 5% had cancers greater than 4 cm in diameter. Of women presenting with other than abnormal Pap smears, 21% had cancers 0 to 2 cm, 26% had cancers 2.1 to 4 cm, and 53% had cancers greater than 4 cm in diameter. Presentation with abnormal Pap smear is significantly associated with tumor size (chi 2 = 25.4, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Do the current standards for glucose tolerance testing in pregnancy represent a valid conversion of O'Sullivan's original criteria?

The venous plasma values for the 100 gm glucose tolerance test endorsed by the Second International Workshop-Conference on Gestational Diabetes represent an arbitrary conversion from O'Sullivan's original values. The latter were calculated from whole blood by means of the Somogyi-Nelson method. The factor used to convert the whole blood values to plasma glucose values was empirically derived in a population in whom pregnancy status was not stated. A conversion factor derived from a nonpregnant population may systematically overestimate plasma glucose concentration when applied to a pregnant population. Paired specimens obtained from 995 consecutive pregnant patients were analyzed by the Somogyi-Nelson method on whole blood and the glucose oxidase method on plasma. A conversion formula was derived and was used to estimate plasma glucose values and 95% confidence limits equivalent to whole blood values. Application of this formula yields plasma glucose oxidase glucose tolerance test values of fasting, 96 mg/dl; 1 hour, 172 mg/dl; 2 hours, 152 mg/dl, and 3 hours, 131 mg/dl. These values are all lower than those currently endorsed.

How reliable is the fifty-gram, one-hour glucose screening test?

The Second International Workshop-Conference on Gestational Diabetes recommended screening all pregnant women with a 1-hour 50 gm oral glucose screening test, given without regard to time of day or time elapsed from the last meal. This study was designed to evaluate the reproducibility of that test, given under those clinical conditions. Thirty women with gestational diabetes and 80 control volunteers between 24 and 28 weeks' gestation were tested at the same time of day on two successive days. Of the 30 women with diabetes, three (10%) had glucose screening test results below the 135 mg/dl threshold on both days and 10 (33%) had results that straddled the threshold on successive days. Test results of 11 control women also straddled the threshold. Among these 21 women with results that straddled the threshold, there was no difference in mean glucose screening test results in diabetic women compared with nondiabetic ones. We conclude that, as currently recommended, the 1-hour glucose screening test is moderately reproducible. Reliance should not be placed on a single normal test result, particularly among patients with risk factors.