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[Clinico-echographic screening in the early diagnosis of prostatic carcinoma. Preliminary results of a feasibility study of a randomized trial].

The preliminary results of a feasibility study of a randomized trial for the early detection of prostate carcinoma are reported. 4,229 healthy men aged 60-75 years were invited to undergo digital rectal examination (DRE) and transrectal ultrasonography (TRUS); 1,284 of them responded and were thus examined. Subjects with suspicious findings at DRE and/or TRUS underwent transperineal US-guided biopsy and prostate-specific antigen (PSA) determination. Subjects with equivocal findings were controlled after 6 months with DRE, TRUS and PSA. The screening program was rather simple (examination time < 10') and cost was limited (cost x subject = US $25). So far, 27 biopsies (2.1%) have been performed. Eighteen cancers have been detected (1.41%), the prevalence/expected incidence ratio being 10.6:1. Stage at diagnosis was B1 in 12, B2 in 3, C in 2 and D in one case, respectively. Cancer had been suspected at DRE in 12, at TRUS in 17 and at PSA (cutoff = 4 micrograms/ml) in 15 of 18 cases, respectively. This study provides evidence that screening for prostate cancer is feasible at a moderate cost and diagnostic anticipation is relevant. A prospective randomized trial is needed to assess whether early detection has any impact at all on mortality. When designing such a study, the effect of compliance, which was low in our experience, on the statistical power should be carefully evaluated. The possibility of pre-screening with PSA, which is much more accepted and might improve attendance rates, should also be evaluated by specific studies.

Aged↗

Sunscreen use and intentional exposure to ultraviolet A and B radiation: a double blind randomized trial using personal dosimeters.

A previous randomized trial found that sunscreen use could extend intentional sun exposure, thereby possibly increasing the risk of cutaneous melanoma. In a similarly designed trial, we examined the effect of the use of sunscreens having different sun protection factor (SPF) on actual exposure to ultraviolet B (UVB) and ultraviolet A (UVA) radiation. In June 1998, 58 European participants 18-24 years old were randomized to receive a SPF 10 or 30 sunscreens and were asked to complete daily records of their sun exposure during their summer holidays of whom 44 utilized a personal UVA and UVB dosimeter in a standard way during their sunbathing sessions. The median daily sunbathing duration was 2.4 hours in the SPF 10 group and 3.0 hours in the SPF 30 group (P = 0.054). The increase in daily sunbathing duration was paralleled by an increase in daily UVB exposure, but not by changes in UVA or UVB accumulated over all sunbathing sessions, or in daily UVA exposure. Of all participants, those who used the SPF 30 sunscreen and had no sunburn spent the highest number of hours in sunbathing activities. Differences between the two SPF groups in total number of sunbathing hours, daily sunbathing duration, and daily UVB exposure were largest among participants without sunburn during holidays. Among those with sunburn, the differences between the two groups tended to reduce. In conclusion, sunscreens used during sunbathing tended to increase the duration of exposures to doses of ultraviolet radiation below the sunburn threshold.

Adolescent↗

Issues in the meta-analysis of cluster randomized trials.

Meta-analyses involving the synthesis of evidence from cluster randomization trials are being increasingly reported. These analyses raise challenging methodologic issues beyond those raised by meta-analyses which include only individually randomized trials. In this paper we review and comment on a selected number of these issues, including problems of study heterogeneity, difficulties in estimating design effects from individual trials and the choice of statistical methods.

Cluster Analysis↗

Randomized trials of high dose chemotherapy for breast cancer.

'Now is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning'Winston Churchill in a speech to the Canadian Senate and House of Commons, December 30, 1941. In laboratory models of cancer, dose of cytotoxic chemotherapy correlates with curative therapy, while cumulative dose is associated with longer survival for those who are not cured. These observations suggests a strategy of using high doses when cure is the objective but smaller doses over a prolonged period when palliation and survival are the goal. A strategy combining repetitive cycles of higher doses of cytotoxic therapy, followed by the optimal combination of hormonal and biological agents based on the tumor's receptors might contribute to both the highest possible cure rate and the longest survival. The development of bone marrow transplant (BMT) for leukemias, and its subsequent modification for support after high dose therapy for other malignancies, has a long, complex and emotional history in medicine. At least partly because of firmly held opinions and the way large randomized trials are funded in the United States, few American randomized trials of BMT or high dose therapy strategies have been completed. The vast majority of published randomized BMT and high dose studies are European. Interestingly, in contrast, two large American randomized trials of high dose chemotherapy for breast cancer had actually completed accrual. Accrual on a third was on target until the presentation of five very small or very early randomized trials at the American Society of Clinical Oncology meeting in May of 1999. Results from some of these trials, which were analyzed after a relatively brief follow-up, are too premature to allow definitive conclusions. Nevertheless, these data have been over and misinterpreted within the scientific and lay communities. The remaining studies included a limited number of patients, thus restricting the statistical power of the observations. The desire for quick answers impeded dispassionate analysis of the available data. The opportunity for collegial review of the data further deteriorated with another round of press coverage when the data from the South African adjuvant study were found to be unreliable. Rather than increasing commitment to accrual on randomized and appropriate pilot trials, accrual to the only large American study in existence at that time trickled to a halt. In response to press coverage, Susan Edmonds from the Fred Hutchinson Cancer Research Center observed that 'the NYT article tends to cast shadows generally on the therapy and those providing the therapy rather than pointing out early in the article (where the public will readily see it) that there are a number of very credible research institutions conducting research directed at breast cancer, some looking at high dose chemotherapy and stem cell transplantation.' Dr. Rodenhuis, presenting the large positive Dutch Randomized study (funded by the Dutch insurance industry) at ASCO in 2000, commented on the 'unreasonably high expectations until 1999' and 'unreasonably negative [opinion-ed] since 1999' for high dose adjuvant chemotherapy for breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗

Does elective sclerotherapy improve the efficacy of long-term propranolol for prevention of recurrent bleeding in patients with severe cirrhosis? A prospective multicenter, randomized trial.

We conducted a prospective, multicenter, randomized trial to compare the efficacy of sclerotherapy plus propranolol with that of propranolol alone in the prevention of recurrent gastroesophageal bleeding in severely cirrhotic patients. For 2 yr (1987 to 1988) 131 patients (96% of whom were alcoholic) with Child-Pugh class B or C cirrhosis (56% were class B and 44% were class C) were randomly assigned to one of our two treatment groups after cessation of variceal bleeding, without hemostatic sclerosis, and were observed for at least 2 yr. Treatment observance was good in 89% of cases; alcohol withdrawal was observed in 62% of cases. Sclerotherapy was performed weekly with 1% polidocanol, and variceal obliteration was obtained in 83% of cases, in a mean number of four sessions. The cumulative percentages (expressed as mean +/- S.D.) of recurrent bleeding at 2 yr were 42% +/- 6% for propranolol plus sclerotherapy and 59% +/- 6% for propranolol alone (a nonsignificant difference). Twenty-eight patients from the propranolol group but only 12 patients from the propranolol-plus-sclerotherapy group had recurrent bleeding from esophageal variceal rupture (p less than 0.01). The total number of blood units per patient with recurrent bleeding was slightly but not significantly more important in the propranolol group (8 +/- 7) than in the propranolol-plus-sclerotherapy group (5 +/- 5; p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Esophageal Diseases↗

Bayesian methods for cluster randomized trials with continuous responses.

Bayesian methods for cluster randomized trials extend the random-effects formulation by allowing both the use of external evidence on parameters and straightforward relaxation of the standard normality and constant variance assumptions. Care is required in specifying prior distributions on variance components, and a number of different options are explored with implied prior distributions for other parameters given in closed form. Markov chain Monte Carlo (MCMC) methods permit the fitting of very general models and the introduction of parameter uncertainty into power calculations. We illustrate these ideas using a published example in which general practices were randomized to intervention or control, and show that different choices of supposedly 'non-informative' prior distributions can have substantial influence on conclusions. We also illustrate the use of forward simulation methods in power calculations with uncertainty on multiple inputs. Bayesian methods have the potential to be very useful but guidance is required as to appropriate strategies for robust analysis. Our current experience leads us to recommend a standard 'non-informative' prior distribution for the within-cluster sampling variance, and an independent prior on the intraclass correlation coefficient (ICC). The latter may exploit background evidence or, as a reference analysis, be a uniform ICC or a 'uniform shrinkage' prior.

Bayes Theorem↗

Evaluation of a healthy-weight treatment program for bulimia nervosa: a preliminary randomized trial.

OBJECTIVE: Conduct a randomized treatment trial to test whether healthy dieting maintains bulimic symptoms or effectively reduces this eating disturbance. METHODS: Female participants (n=85) with full- and sub-threshold bulimia nervosa were randomly assigned to a 6-session healthy dieting intervention or waitlist condition and assessed through 3-month follow-up. RESULTS: Relative to control participants, intervention participants showed modest weight loss during treatment and demonstrated significant improvements in bulimic symptoms that persisted through follow-up. DISCUSSION: These preliminary results suggest that this intervention shows potential for the treatment of bulimia nervosa and may be worthy of future refinement and evaluation. Results also provide experimental evidence that dieting behaviors do not maintain bulimia nervosa, suggesting the need to reconsider maintenance models for this eating disorder.

Adolescent↗

Prostate specific antigen testing and digital rectal examination before and during a randomized trial of screening for prostate cancer: European randomized study of screening for prostate cancer, Rotterdam.

PURPOSE: Worldwide 2 large-scale randomized screening trials for prostate cancer have been initiated. Determining prostate specific antigen (PSA) involves a simple test that may influence the outcome of these trials if frequently done in the control arm or before study enrollment. We quantified PSA and digital rectal examination before and during the screening trial in Rotterdam, The Netherlands and in the general population. MATERIALS AND METHODS: Trial participants were administered study intake questionnaires on tests done before study participation. Data on PSA from the regional general practice laboratory were correlated with participant data. Various sources were used to quantify PSA tests and digital rectal examinations in the general population. RESULTS: Of men 55 to 74 years old 45% underwent digital rectal examination at 1 time and 13% reported that PSA was tested before trial participation. Each rate increased with age. No statistically significant effect of former PSA testing or digital rectal examination on the cancer detection rate was identified. The rate of PSA determination after initial screening and/or randomization in the control arm was 2-fold that in the screening arm (76 versus 33/1,000 person-years). PSA determination initially decreased in the screening arm but increased rapidly after some time. The number of PSA determinations in the general population was estimated to be 45/1,000 person-years at ages 55 to 69 years. CONCLUSIONS: PSA testing was moderate in the control arm but if different men undergo this test each year, the contamination rate may become rather high. In the final analysis of mortality PSA testing should be considered.

Adult↗

Outpatient treatment of cervical intra-epithelial neoplasia. The CO2 laser versus cryotherapy, a randomized trial.

In a randomized study, 204 patients were allocated to either laser or cryo treatment for cervical intra-epithelial neoplasia (CIN). The patients were treated on an outpatient basis without anesthesia unless other conditions requiring anesthesia had to be dealt with at the same time. Both the laser and the cryo method were highly acceptable to the patients. Slightly more patients experienced moderate or severe pain during laser treatment, compared with cryo treatment (P = 0.05). Peroperative hemorrhage did not exceed 25 cc except for one laser-treated patient. Postoperative vaginal discharge was more often seen after cryo coagulation, the discharge being malodorous in 36% of cryo-treated patients and in 17% of laser-treated patients. Pelvic inflammatory disease was found in one patient in each treatment group. Postoperative spotting occurred more often in laser-treated patients (49%) than in cryo-treated patients (22%). At follow-up colposcopy 3 months after treatment, the squamocolumnar junction was fully visible significantly more often in laser-treated patients (P less than 0.001). The cure rates after one laser or cryo treatment were 90% and 91%, respectively. Subsequent to 19 initial treatment failures, 8 patients have at present been retreated with the same method as initially used, and all 8 are cured. The cure rates after one or two treatments are 96% in the laser group and 93% in the cryo group. The rates are preliminary, due to the short observation time. Publications will appear when all patients have been followed for 2 and 5 years.

Adult↗

Effectiveness of hospital-based geriatric evaluation and management and home intervention team (GEM-HIT). Rationale and design of a 5-year randomized trial.

In this ongoing randomized controlled trial the effectiveness of an interdisciplinary team implementing hospital-based comprehensive geriatric assessment (CGA) and home intervention is being studied. All patients admitted from home showing functional decline with impairment of any basic activity of daily living are randomly assigned to one of the following courses of treatment: CGA with in-hospital and post discharge management by a home intervention team (HIT), where necessary (group 1): CGA with recommendations and usual care at home (group 2); or usual hospital and home care (group 3). The HIT consists of 3 nurses, 1 geriatrician, 1 physiotherapist, 1 occupational therapist, and 1 social worker. 540 patients will be recruited for the trial, which will assess the effects of GEM-HIT on the following outcomes: health status, functional status, survival, hospital readmission, nursing home placement and costs. The purpose of the GEM-HIT trial is to answer many of the current questions concerning treatment and health care delivery for frail older persons under the specific conditions found in Germany. The large sample size and the broad range of diagnoses included in the study will allow the evaluation of effects of GEM-HIT for subgroups and may help to identify the most effective assessment tools for use within our particular context.

Activities of Daily Living↗

Contraceptive effectiveness of two spermicides: a randomized trial.

OBJECTIVE: We conducted a multinational randomized trial to determine whether a spermicidal film containing 72 mg of nonoxynol-9 per film was at least as effective in preventing pregnancy as a foaming tablet containing 100 mg of nonoxynol-9 per tablet. METHODS: Between September 1995 and July 1997, 765 women aged 18-35 years who had no evidence of subfecundity were randomly assigned to use one of the two spermicides as their only contraceptive method at every coital act for 28 weeks. Participants were asked to keep coital diaries throughout the study period. Pregnancy tests were performed on a scheduled basis. Each participant was followed for 28 weeks or until she stopped considering the spermicide as her primary method of contraception. RESULTS: The Kaplan-Meier estimate of the 6-month probability of pregnancy during typical use of the spermicide was 28.0% in the tablet group and 24.9% in the film group (P = .78, one-tailed test). The study had nearly 75% power to have detected a difference of seven percentage points between groups. Results were almost identical when the analysis included only months when the participants reported use of the spermicide during every coital act. Reported levels of sexual activity and compliance with use of the spermicide were high in both groups. CONCLUSION: The contraceptive effectiveness of these two spermicidal products appeared similar. Both products were associated with a fairly high risk of pregnancy in this young, highly sexually active population.

Adolescent↗

Randomized trials of aminoglycoside antibiotics: quantitative overview.

Individual randomized trials comparing aminoglycosides have usually involved a sample size inadequate for reliable detection of small to moderate differences. In a search for overall effects that might not be apparent from any single trial, a quantitative overview of all randomized studies comparing amikacin, gentamicin, netilmicin, sisomicin, and tobramycin was performed. These aminoglycosides appeared equally efficacious, except that tobramycin seemed less effective than sisomicin. Patients given gentamicin or sisomicin seemed to run a higher risk of nephrotoxicity than those given amikacin; the risk for patients receiving tobramycin was lower than that for patients given gentamicin but higher than that for those given netilmicin. The only statistically significant difference with regard to auditory toxicity was a lower risk among patients receiving netilmicin than among those given amikacin or tobramycin. Meaningful differences in toxicity may exist for individual aminoglycosides given in efficacious doses. Future trials must include sample sizes sufficient to detect differences of the magnitudes observed in this overview. In the absence of such data, the overview may guide clinicians in determining the risk-to-benefit ratio for a particular aminoglycoside, especially for patients at high risk of toxicity.

Aminoglycosides↗

GnRH antagonist-induced inhibition of the premature LH surge increases pregnancy rates in IUI-stimulated cycles. A prospective randomized trial.

BACKGROUND: Our prospective randomized controlled trial was designed to assess whether the use of GnRH antagonists can improve the success rate of controlled ovarian stimulation (COS)/intrauterine insemination (IUI) treatments, via inhibition of the premature LH rise. METHODS: A total of 104 patients were randomly divided, using a randomization list, into two groups: in group A (n = 52), recombinant FSH (rFSH) was given with GnRH antagonist Cetrorelix, and in group B (n = 52), the patients received rFSH alone in a manner similar to that of group A. The primary outcome measure was clinical pregnancy rate per couple. RESULTS: The pregnancy rate per patient was 53.8% in group A and 30.8% in group B (P = 0.017). The rate of premature LH surge was 7% in group A and 35% in group B (P < 0.0001). A premature luteinization was observed in two cycles of 144 in group A (1.4%) and in 16 cycles of 154 in group B (10.4%) (P = 0.001). The mean values of LH and progesterone were significantly lower in patients receiving GnRH antagonist than in those who did not (3.3 +/- 3.3 mIU/ml in group A versus 9.9 +/- 7.9 mIU/ml in group B, P < 0.0001, for LH; 1.3 +/- 1.1 ng/ml versus 2.1 +/- 1.9 ng/ml for group A and B, respectively, P < 0.0001, for progesterone). CONCLUSION: The use of GnRH antagonist in COS/IUI cycles improves pregnancy rate, preventing the premature LH rise and luteinization.

Cost-Benefit Analysis↗

Immediate anticoagulation of embolic stroke: a randomized trial. Cerebral Embolism Study Group.

A randomized trial of immediate versus delayed anticoagulation of patients with cardiogenic embolic brain infarction was carried out in a multi-centered study. Patients who were within 48 hours of onset of deficit and who had no evidence of hemorrhage on computed tomography (CT) were randomized to receive either immediate heparinization or no anticoagulants for the initial 14 days following stroke. There were 63 patients with embolic stroke identified during the study period. Eighteen patients were not randomized because of specific exclusion criteria or delayed identification more than 48 hours after stroke. Of 45 patients who were randomized, 44 patients (98%) completed the initial week of the protocol: 24 were immediately heparinized at an average of 32 hours after stroke, 21 received no immediate anticoagulation. Two patients developed delayed hemorrhagic infarction and two patients experienced early recurrent embolism, all among the nonanticoagulated group. Of all patients with embolic stroke who were not receiving coumadin at onset of stroke, only two of 56 (4%) had hemorrhagic infarction on initial CT. Follow-up CT in 40 of these patients showed late developing hemorrhagic infarction in two additional patients (5%). All four hemorrhagic infarctions occurred in 18 non-anticoagulated patients with large infarcts. There were no major complications associated with immediate heparinization of 24 unselected patients with all sizes of embolic infarction. A trend toward reduction of early recurrent embolism was apparent. These data support immediate anticoagulation of nonhypertensive patients with embolic brain infarction who have no evidence of hemorrhage on CT performed 24-48 hours after stroke.

Adult↗

Likelihood methods for treatment noncompliance and subsequent nonresponse in randomized trials.

While several new methods that account for noncompliance or missing data in randomized trials have been proposed, the dual effects of noncompliance and nonresponse are rarely dealt with simultaneously. We construct a maximum likelihood estimator (MLE) of the causal effect of treatment assignment for a two-armed randomized trial assuming all-or-none treatment noncompliance and allowing for subsequent nonresponse. The EM algorithm is used for parameter estimation. Our likelihood procedure relies on a latent compliance state covariate that describes the behavior of a subject under all possible treatment assignments and characterizes the missing data mechanism as in Frangakis and Rubin (1999, Biometrika 86, 365-379). Using simulated data, we show that the MLE for normal outcomes compares favorably to the method-of-moments (MOM) and the standard intention-to-treat (ITT) estimators under (1) both normal and non-normal data, and (2) departures from the latent ignorability and compound exclusion restriction assumptions. We illustrate methods using data from a trial to compare the efficacy of two antipsychotics for adults with refractory schizophrenia.

Algorithms↗

Concomitant versus sequential administration of epirubicin and paclitaxel as first-line therapy in metastatic breast carcinoma: results for the Gruppo Oncologico Nord Ovest randomized trial.

BACKGROUND: The authors performed a randomized trial comprising patients with metastatic breast carcinoma (MBC). They used a noninferiority design to evaluate whether the results of sequential administration of epirubicin and paclitaxel were not markedly worse than the concomitant administration in terms of objective response rates (ORRs). Toxicity profile, quality of life (QOL), and pharmacoeconomic evaluations were evaluated as well. METHODS: In the current study, 202 patients with MBC were randomized to receive either the combination of epirubicin at a dose of 90 mg/m2 plus paclitaxel at a dose of 200 mg/m2 for 8 cycles (concomitant arm, n = 108) or epirubicin at a dose of 120 mg/m2 for 4 cycles followed by paclitaxel at a dose of 250 mg/m2 over 3 hours for 4 cycles every 21 days (sequential arm, n = 94). RESULTS: The authors rejected the null hypothesis that the sequential treatment is less active than the standard concomitant regimen (ORRs: concomitant = 58.5%, sequential = 57.6%). The median progression-free and overall survival periods were 11.0 months (95% confidence interval [95% CI], 9.7-12.3) and 20.0 months (95% CI, 17.2-22.6), respectively, in the concomitant arm and 10.8 months (95% CI, 7.9-13.6) and 26 months (95% CI, 18.1-33.8), respectively, in the sequential arm (P = not significant). Patients who received the sequential regimen experienced a higher incidence of Grade 3/4 (according to the World Health Organization grading system) neutropenia (62.2% of courses vs. 50.62%; P = 0.003) and Grade > or = 2 neuropathy (45.5% vs. 30.4% of patients; P = 0.03), whereas 6 patients who received the concomitant regimen developed Grade II cardiotoxicity according to New York Heart Association criteria. QOL analyses failed to provide clear differences. CONCLUSIONS: The sequential administration of epirubicin and paclitaxel at full doses was found to be as active as their association. Therefore, both the sequential and the combined administration were acceptable options.

Adult↗

Meta-analyses of randomized trials comparing different doses of mifepristone in emergency contraception.

There is some evidence from randomized trials that different doses of mifepristone for emergency contraception do not differ in efficacy in the range from 10 mg to 600 mg. Lower doses have a better side effect profile and are cheaper and therefore they would be preferable in the absence of a dose effect. However, the lack of significance is not evidence of absence of an effect. More evidence can be obtained by combining results of trials. We present meta-analyses of randomized trials comparing doses of mifepristone for emergency contraception from 5 mg to 600 mg, with regard to the efficacy to prevent unwanted pregnancies. We use two approaches for analysis, one using only within-trial information and another one combining within-trial with between-trial information. We discuss the results in terms of equivalence. There is some evidence of a small dose effect on efficacy in the lower range of doses (<50 mg). The pregnancy rate increases by a factor of 1.6 when the dose of 10 mg is used instead of 25 mg (95% confidence interval: 1.1-2.4). In terms of the number of women needed to treat, however, using 10 mg in the place of 25 mg implies having one extra pregnancy every 146 women requesting emergency contraception, which might be a low cost compared to the benefit of more women having access to treatment.

Adult↗

Effect of air filtration systems on asthma: a systematic review of randomized trials.

STUDY OBJECTIVES: To systematically review the evidence of randomized trials evaluating the effects of residential air filtration systems on patients with asthma. DATA SOURCES: We searched for published and unpublished studies using MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Collaboration. We reviewed all reference lists for additional articles of relevance, and contacted experts in the field and air filter manufacturers. STUDY SELECTION: We identified 10 relevant randomized controlled trials that examined the influence of a residential air filtration system on patients with asthma. DATA EXTRACTION: In duplicate and independently, we abstracted data on the methodologic quality, population, intervention, and outcomes. DATA SYNTHESIS: Five of 10 studies enrolled adults only. One study included children only. The sample size ranged from 9 to 45 participants in each study, for a total of 216 patients across all studies. Two studies reported a statistically significant decrease in airway responsiveness associated with air filter utilization. Air filters were associated with significantly lower total symptom scores (weighted mean difference of 0.47; 95% confidence interval [CI], 0.69 to 0.25) on a 10-point scale, and lower sleep disturbance score (weighted mean difference of 0.93; 95% CI, 1.44 to 0.42); however, heterogeneity of results weakens the inferences from these trials. Air filtration systems were not associated with any differences in medication use or morning peak expiratory flow values. None of these trials employed validated scales to measure clinical symptoms or quality of life. CONCLUSIONS: Among patients with allergies and asthma, use of air filters is associated with fewer symptoms. Rigorous sufficiently powered randomized clinical trials are needed to more precisely define the influence of air filtration on health-related quality of life and symptom control for asthmatic patients.

Air Conditioning↗