Methods of joint evaluation of efficacy and toxicity in phase II clinical trials.

Phase II clinical trials in oncology are usually conducted to evaluate the anti-tumor effect. Because phase I trials are small studies, the maximum tolerated dose of a new drug may not be precisely established and the recommended dose used may lead to excessive toxicity. We investigate the methods proposed by Conaway-Petroni and Bryant-Day allowing early termination of phase II clinical trials and based on joint evaluation of treatment efficacy and safety. Both study designs are computed to minimize the expected accrual under the null hypothesis. As two criteria are considered, the null hypothesis is an area. Each method defines two specific type I error risks. Bryant-Day demonstrate that response and toxicity may be considered as independent (Phi=1). We compare the properties of these two methods with exact calculation according to objective criteria and present one example from a study conducted in France. The two methods differ with regard to the definition of the risks and the assumption of independence. They are similar in terms of expected accruals when Phi=1. Deviations from the assumption of independence induce minor consequences on the type I error risks when the constraint on the type II error risk is less than 15%. Choosing Phi has a minimal impact on expected accrual. Finally, one type I error risk (alpha00) defined by Conaway-Petroni dramatically increases in the case of deviation from the assumption made on Phi. Due to its robustness in relation to a deviation from the independence assumption, we recommend the use of the Bryant-Day method in clinical practice.

ACL reconstruction: a meta-analysis of functional scores.

From individual randomized studies, it is unclear whether patellar tendon grafts or hamstring tendon grafts yield the best functional results after ACL reconstruction. Therefore, we performed a meta-analysis to provide quantitative data to compare patellar with hamstring grafts after ACL reconstruction with regard to knee function. We searched computerized databases for randomized controlled trials reporting one of the following outcomes related to function: final overall International Knee Documentation Committee score and return to preinjury level of activity. Studies were abstracted independently by two reviewers. Random effect models were used to pool the data. Fourteen trials (1263 patients) met the inclusion criteria. We found no difference in final overall International Knee Documentation Committee score or in the number of patients returning to full activity after patellar and hamstring graft reconstruction. Relative risk was 0.90 for final overall International Knee Documentation Committee Class A and 0.94 for return to preinjury level of activity in favor of patellar grafts. Quantitative interaction tests on the effect of treatment based on study quality, randomization status, number of strands used, and length of followup were non significant. At last followup, only 41% and 33% of patients, respectively, had patellar and hamstring grafts reconstructed reported as normal based on the final overall International Knee Documentation Committee score.

Diagnosis of vertebral fractures by vertebral fracture assessment.

Vertebral fractures are independent risk factors for both vertebral and peripheral fractures and only one-third of these fractures come to clinical attention. Vertebral fracture assessment (VFA) is a radiographic method using dual X-ray absorptiometry (DXA) to assess vertebral deformities during bone density measurement. We performed VFA of the spine from T4 to L5 on a Delphi W device (Hologic, Bedford, MA) in 136 postmenopausal patients (69+/-10 yr). These patients also had X-rays of the thoracic and lumbar spine. VFA was independently compared with X-rays by two rheumatologists, for the diagnosis of vertebral fractures at both the patient and vertebral levels. Using X-rays, 61 patients (45%) had at least one vertebral fracture. The percentage of unreadable vertebrae was 1% and 12.4% on X-rays and VFA, respectively (p<0.0001). At the patient level, VFA allowed to diagnose if the patient had no fracture or had at least one fracture in 74% of patients. In 11.2% of cases, VFA misclassified the patients. At the vertebral level, diagnostic efficacy of VFA as compared with X-rays was 97%. Concordance between both observers was good (kappa-score=0.69). We designed an algorithm for decision of performing X-rays in postmenopausal women: Using results of VFA would avoid X-rays in 32% of our patients. VFA is a reliable technique with low radiation, and is easily and rapidly applicable during bone density measurement by DXA, which could improve management of osteoporotic patients.

Bone-patellar tendon-bone autografts versus hamstring autografts for reconstruction of anterior cruciate ligament: meta-analysis.

OBJECTIVES: To compare bone-patellar tendon-bone autografts with hamstring autografts for reconstruction of the anterior cruciate ligament. DATA SOURCES: Medline, WebSPIRS, Science Citation Index, Current Contents databases, and Cochrane Central Register of Controlled Trials. Review methods All randomised controlled trials reporting one or more outcome related to stability (instrumented measurement of knee laxity, Lachman test, or pivot shift test) and morbidity (anterior knee pain, kneeling test, loss of extension, or graft failure). Study quality was assessed by using a 5 point scale. Random effect models were used to pool the data. Heterogeneity in the effect of treatment was tested on the basis of study quality, randomisation status, and number of tendon strands used. RESULTS: 24 trials of 18 cohorts (1512 patients) met the inclusion criteria. Study quality was poor for nine studies and fair for nine studies. The weighted mean difference of the instrumented measurement of knee laxity was 0.36 (95% confidence interval 0.01 to 0.71; P = 0.04). Relative risk of a positive Lachman test was 1.22 (1.01 to 1.47; P = 0.04), of anterior knee pain 0.57 (0.44 to 0.74; P < 0.0001), of a positive kneeling test 0.26 (0.14 to 0.48; P < 0.0001), and of loss of extension 0.52 (0.34 to 0.80; P = 0.003). Other results were not significant. CONCLUSION: Morbidity was lower for hamstring autografts than for patellar tendon autografts. Evidence that patellar tendon autografts offer better stability was weak. The poor quality of the studies calls into question the robustness of the analyses.

Factors influencing inclusion of patients with malignancies in clinical trials.

Participation in clinical trials remains low and is a central issue in oncology. The authors identified, through a systematic review, 75 papers published up to August 2004 that report barriers to recruitment of patients in clinical trials. These barriers range from patient preference and concern about information/consent to clinical problems with protocols. Strategies to overcome barriers on the part of patients and clinicians are needed and should be carefully evaluated. Thirty-three (44%) papers reported factors related to patients as influencing the inclusion of patients, 28 (37%) reported clinician's related factors, and 37 (49%) other factors from either specific groups of patients (30 papers, 40%) and/or other scopes (13 papers, 17%). No differences in prevalence were found between papers dedicated to hematologic malignancies and solid tumors. Factors related to clinicians as influential were more frequently reported before 1995 (70%) than thereafter (25%; P = 0.0009). Reporting specific groups of patients as influential was more frequent in North American articles (50%) than in others (14%, P = 0.008). Patients' barriers included mostly patient preference (12 papers), concern about information and/or consent (11 papers), worry about uncertainty (7 papers), and/or relationship with medical team (7 papers). Concerning clinicians, incompatibility of protocol with normal practice (nine papers), problems in complying with the protocol (eight papers), and/or consent procedure (eight papers) were the most reported factors. The remaining factors mostly relied on specific groups of patients (30 papers), notably age of patients (18 papers) and/or minority population (11 papers, all from the USA). Strategies to overcome these barriers are needed and should be carefully evaluated.

[Treatment interruption in 30 HIV-infected patients with successful viral suppression under highly active antiretroviral treatment]. / Interruptions du traitement antirétroviral chez 30 patients infectés par le VIH en succès virologique.

OBJECTIVE: To evaluate clinical and laboratory results in HIV-infected patients with complete viral suppression under HAART (highly active antiretroviral treatment) for whom treatment was interrupted and to identify risk factors associated with prolonged (i.e., successful) treatment interruption. METHODS: Retrospective study of patients who interrupted therapy while on HAART with a plasma HIV RNA <400 copies/mL. Multivariate regression analysis was performed to identify factors associated with a prolonged interruption (more than 6 months). RESULTS: 36 treatment interruptions in 30 patients were analyzed. Patients' mean age was 42 years, 83% were men, and 60% were infected through homosexual contact. Median CD4 cell count at initiation of HAART was 292/mm3 and median viral load 43,000 copies/mL. Reported reasons for HAART discontinuation included patient or clinician choice (n=21) or drug toxicity (n=15). Median CD4 cell count when treatment interruption began was 606/mm3, and its median duration was 14 months. During treatment interruption, adverse clinical events or laboratory findings occurred in 9 patients (30%), all of whom had a CD4 cell count nadir < 300/mm3. When HAART resumed, median CD4 cell count was 302/mm3, and median viral load 59,800 copies/mL. Plasma HIV RNA dropped to <400 copies/mL in all patients within 4 months of resuming treatment. In multivariate analysis, the factors associated with resuming HAART within 6 month of treatment interruption were: HAART including non-nucleoside analog (adjusted Hazard Ratio [aHR]: 3.6, 95% CI: 1.2-10.6, p = 0.02), a CD4 cell count nadir < 300 (adjusted Hazard Ratio [aHR]: 5.5, 95% CI: 2.0-26, p = 0.0057), undetectable plasma HIV RNA for longer than 21 months at the interruption (aHR: 7.2, 95% CI: 2-26, p = 0.002). This probability was 45.5% in patients with a CD4 cell count nadir < 300 and 14.3% in the others (p 0.10). CONCLUSION: Antiretroviral treatment should be interrupted only with caution in patients with a CD4 cell count nadir <300/mm3 because of the risk of adverse clinical events or laboratory findings.

Exposure over the life course to an urban environment and its relation with obesity, diabetes, and hypertension in rural and urban Cameroon.

BACKGROUND: This study aimed to assess the association between lifetime exposure to urban environment (EU) and obesity, diabetes, and hypertension in an adult population of Sub-Saharan Africa. METHODS: We studied 999 women and 727 men aged > or =25 years. They represent all the adults aged > or =25 years living in households randomly selected from a rural and an urban community of Cameroon with a 98% and 96% participation rate respectively. Height, weight, blood pressure, and fasting blood glucose were measured in all subjects. Current levels of physical activity (in metabolic equivalents [MET]) were evaluated through the Sub-Saharan African Activity Questionnaire. Chronological data on lifetime migration were collected retrospectively and expressed as the total (EUt) or percentage (EU%) of lifetime exposure to urban environment. RESULTS: Lifetime EUt was associated with body mass index (BMI) (r = 0.42; P < 0.0001), fasting glycaemia (r = 0.23; P < 0.0001), and blood pressure (r = 0.17; P < 0.0001) but not with age. The subjects who recently settled in a city (< or =2 years) had higher BMI (+2.9 kg/m(2); P < 0.001), fasting glycaemia (+0.8 mmol/l; P < 0.001), systolic (+23 mmHg; P < 0.001) and diastolic (+9 mmHg; P = 0.001) blood pressure than rural dwellers with a history of 2 years EU. EU during the first 5 years of life was not, on its own, associated with glycaemia or BMI. However, both lifetime EUt and current residence were independently associated with obesity and diabetes. The association between lifetime EUt and hypertension was not independent of current residence and current level of physical activity. CONCLUSIONS: This study suggests that for the study of obesity and diabetes, in addition to current residence, both lifetime exposure to an urban environment and recent migration history should be investigated.