Measles outbreak in Surrey.
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Disease Outbreaks↗
Biomedical subjects
Kevin Carroll
Publications and source records attributed to Kevin Carroll.
Optimizing randomized phase II trials assessing tumor progression.
The traditional development paradigm for phase II trials in oncology has been challenged in recent years by the introduction of cytostatic therapies. These agents slow the growth of tumors rather than cause high rates of shrinkage, this argues for the use of endpoints that measure growth inhibition such as progression free survival. We have previously argued the need for randomized trials in this setting. Here we discuss methodological solutions to enhance the development decision at the end of phase II in the context of progression endpoints employed in randomized trials. There are well recognized issues associated with progression endpoints relating to bias in the timing and interpretation of assessments. In this paper we present design and analysis solutions that will minimize bias by using methods that are either partially or completely time independent. We also discuss other design features to maximize the information yielded in a phase II setting. We advocate the creation of progression endpoints that utilize all available progression data rather than early fixed time-point analyses and show that little is to be gained by assessing progression status any more frequently than would be required in routine clinical practice. Such design and analysis measures will optimize the development decision made at the end of phase II clinical evaluation.
Algorithms↗
Lower extremity socket design and suspension.
The availability of advanced materials and techniques means that lower extremity prosthetic users of all ages and amputation levels can achieve a more complete lifestyle recovery. The key component of any lower extremity prosthesis is the socket. The socket is the foundation for the user's comfort, and comfort is the foundation for restoring a individual's mobility. Dynamic sockets, "high-tech" liners, and individualized fitting practices are key elements in achieving comfort. Various available suspension systems address the needs of virtually all users. Finally, emerging technologies indicate an even brighter future for all individuals who use a lower extremity prosthesis (Fig. 13).
Amputation, Surgical↗
Prophylactic breast irradiation with a single dose of electron beam radiotherapy (10 Gy) significantly reduces the incidence of bicalutamide-induced gynecomastia.
PURPOSE: To evaluate the efficacy and tolerability of prophylactic breast irradiation in reducing the incidence and severity of bicalutamide-induced gynecomastia and breast pain. METHODS AND MATERIALS: In all, 106 men with prostate cancer (T1b-T4/Nx/M0) and no current gynecomastia/breast pain were enrolled in this randomized, sham-controlled, double-blind, parallel-group multicenter trial. Patients received either a single dose of electron beam radiotherapy (10 Gy) or sham radiotherapy. Bicalutamide (Casodex) 150 mg/day was administered for 12 months from the day of radiotherapy. Every 3 months, patients underwent physical examination and questioning about gynecomastia and breast pain. RESULTS: The incidence of investigator-assessed gynecomastia was significantly lower with radiotherapy vs. sham radiotherapy (52% vs. 85%; odds ratio [OR], 0.13; 95% confidence interval [CI], 0.04, 0.38; p < 0.001); direct questioning showed similar results. Fewer radiotherapy patients had >/=5 cm gynecomastia (measured by calipers; 11.5% vs. 50.0% for sham radiotherapy), and fewer cases were moderate-to-severe in intensity (21% vs. 48%). Similar proportions of radiotherapy and sham radiotherapy patients experienced breast pain (83% vs. 91%; OR, 0.25; 95% CI, 0.05, 1.27; p = 0.221); patients receiving radiotherapy experienced some reduction in its severity (OR, 0.44; 95% CI, 0.20, 0.97; p = 0.0429). CONCLUSIONS: Prophylactic breast irradiation is an effective and well-tolerated strategy for prevention of bicalutamide-induced gynecomastia.
Aged↗
Design and analysis of non-inferiority mortality trials in oncology.
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Antineoplastic Agents↗
Is the efficacy of hormonal therapy affected by lymph node status? data from the bicalutamide (Casodex) Early Prostate Cancer program.
OBJECTIVES: To report an exploratory subgroup analysis assessing the extent to which the overall benefit found in the Early Prostate Cancer program is dependent on lymph node status at randomization. The program is ongoing, and the overall survival data are immature. The first combined analysis of the bicalutamide (Casodex) Early Prostate Cancer program at 3 years' median follow-up showed that bicalutamide, 150 mg once daily, plus standard care (radical prostatectomy, radiotherapy, or watchful waiting), significantly reduced the risk of objective progression and prostate-specific antigen (PSA) doubling in patients with localized/locally advanced prostate cancer. METHODS: Men (n = 8113) with localized/locally advanced disease received bicalutamide 150 mg or placebo once daily, plus standard care. The time to event data (objective progression, PSA doubling) was analyzed by lymph node status at randomization. RESULTS: Compared with standard care alone, bicalutamide significantly reduced the risk of objective progression, irrespective of lymph node status, with the most pronounced reduction in patients with N+ (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.15 to 0.56) compared with those with N0 (HR 0.59; 95% CI 0.48 to 0.73) and Nx (HR 0.60; 95% CI 0.50 to 0.72) disease. The largest decrease in risk of PSA doubling with bicalutamide was observed in N+ disease (HR 0.16; 95% CI 0.09 to 0.29), with significantly reduced risks seen in N0 (HR 0.45; 95% CI 0.40 to 0.51) and Nx (HR 0.38; 95% CI 0.33 to 0.44) disease. CONCLUSIONS: The greatest reduction in the risk of objective progression and PSA doubling with bicalutamide was seen in patients with N+ disease. However, bicalutamide also provided a statistically significant benefit in those with N0 and Nx disease.
Adult↗
Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6.
PURPOSE: We evaluated the benefits of adding 150 mg bicalutamide to standard care, that is radical prostatectomy, radiotherapy or watchful waiting (WW), in patients with localized or locally advanced prostate cancer. MATERIALS AND METHODS: A total of 1,218 men with T1-4, M0, any N prostate cancer were recruited from 62 Scandinavian centers and randomized 1:1 to 150 mg bicalutamide or placebo plus standard care. Primary end points were progression-free survival (PFS) and overall survival. RESULTS: At a median 5.3-year followup patients with locally advanced disease had improved survival with bicalutamide (HR 0.68, 95% CI 0.50 to 0.92), while those with localized disease had decreased survival with bicalutamide (HR 1.47, 95% CI 1.06 to 2.03). Bicalutamide significantly improved PFS, decreasing the risk of disease progression by 43% compared with placebo (HR 0.57, 95% CI 0.48 to 0.68, p<0.0001). The rate of events was 35.4% for bicalutamide and 46.2% for placebo. Patients with locally advanced disease gained the greatest PFS benefits with bicalutamide (HR 0.40, 95% CI 0.31 to 0.52). Since 81% of the trial population were untreated before entry and would otherwise have undergone WW, the findings essentially reflect the results of immediate hormone therapy vs WW. CONCLUSIONS: Bicalutamide (150 mg) provides significant benefit in patients with locally advanced disease. In previously untreated patients there may be a tumor burden below which endocrine therapy provides no benefit or may even decrease survival.
Aged↗
Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years.
PURPOSE: We evaluated the efficacy and tolerability of 150 mg bicalutamide daily given in addition to standard care, in patients with localized or locally advanced prostate cancer. MATERIALS AND METHODS: The bicalutamide Early Prostate Cancer program consists of 3 randomized, double blind, placebo controlled trials prospectively designed for combined analysis. A total of 8,113 men with T1b-T4, M0, any N (N0 in 1 trial) prostate cancer were randomized to bicalutamide 150 mg/day (4,052) or placebo (4,061) in addition to standard care (radical prostatectomy, radiotherapy or watchful waiting). Primary end points were objective progression-free survival (PFS) and overall survival. RESULTS: At median 5.4 years of followup (21.6% progression events) bicalutamide significantly improved PFS in the overall population. This result was driven by positive results in trials 24 and 25, with the North American trial (trial 23) showing no difference. Patients with locally advanced disease gained most benefit from bicalutamide in terms of PFS, irrespective of underlying therapy. Overall survival was similar in the bicalutamide and placebo groups, across the program and in each trial. Among watchful waiting patients survival appeared to be improved with bicalutamide in those with locally advanced disease, whereas survival appeared to be reduced with bicalutamide in those with localized disease. The most common adverse events with bicalutamide were gynecomastia and breast pain. Other adverse events occurred with a similarly low incidence in the 2 treatment groups. CONCLUSIONS: This analysis confirms that bicalutamide provides benefit in patients with locally advanced disease. The current data suggest that early or adjuvant hormonal therapy for patients at low risk of disease progression, such as those with localized disease, is not appropriate.
Adult↗
The epidemiology of the comorbidity of epilepsy in the general population.
PURPOSE: To describe the epidemiology of somatic and psychiatric conditions in adults with epilepsy in the community and compare it to that of people without epilepsy. METHODS: A cross-sectional population-based study extracting data from the UK General Practice Research Database for the period 1995-1998. Age- and sex-standardized prevalence rates were estimated for selected conditions and groups of conditions (categorized by ICD-9 chapters) in adults with epilepsy registered with primary care physicians. Results were compared with those in adults without epilepsy in the cohort, and prevalence ratios were calculated according to two broad age groups (16-64 and older than 64 years). RESULTS: Conditions common in the general population also were common in adults with epilepsy. Psychiatric disorders occurred twice as often, and the risk of somatic disorders was increased in people with epilepsy, with the exception of musculoskeletal and connective tissue disorders in older adults. The prevalence ratio of neoplasia, excluding intracranial tumors, was not increased in epilepsy. The prevalence ratio of brain tumors was particularly increased in young adults [prevalence ratio (PR), 70.7] and of meningiomas in older adults (PR, 91.9). Neurodegenerative conditions, particularly dementias and Alzheimer' disease (PR, 6.3 and 8, respectively) and Parkinson' disease (PR, 3.2), appeared more frequently in people with epilepsy. Upper gastrointestinal bleed occurred more frequently in epilepsy (PR, 4.3), as did cardio- and cerebrovascular disorders, fractures, pneumonia and chronic lung diseases, and diabetes. Eczema, osteoarthritis, and rheumatoid arthritis did not occur more frequently in epilepsy. CONCLUSIONS: The prevalence ratio of many common psychiatric and somatic conditions is increased in adults with epilepsy who consult a primary care physician in the U.K. These findings may have implications in the diagnosis and management of epilepsy and coexisting conditions, as well as in health care provision.
Adolescent↗
Comparison of outcomes from a district tuberculosis control programme in the Pacific: before and after the implementation of DOTS.
Outcomes are compared for a district tuberculosis (TB) control programme, before and after DOTS (directly observed therapy short-course) and a computerized register were introduced. There were significant improvements in case holding associated with the interventions. The successful treatment rate was 13.6% [95% CI (confidence interval), 4.9-23.0] higher and the default rate 9.6% (95% CI, 3.6-17.3) lower following the introduction of DOTS and the computerized register. There was no difference in cure rates or death rates, the notification of new cases, the proportion of pulmonary cases or sputum positives. Additional benefits associated with the computerized register were improvements in supervision, reporting and statistical analysis. The short-course chemotherapy permitted flexibility and was well accepted by both health staff and patients. This study demonstrates that computerization of TB registration using appropriate software is feasible in district TB programmes in resource poor countries and can contribute to improving their performance.
Antitubercular Agents↗
Association between practice size and quality of care of patients with ischaemic heart disease: cross sectional study.
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Cross-Sectional Studies↗
Referral of children to specialists in the United States and the United kingdom.
OBJECTIVE: To compare the rates and patterns of children's specialty referrals in the United States (US) and the United Kingdom (UK). DESIGN: Retrospective cohort analysis of health care claims/encounter data obtained in 1996 (US) and 1997 (UK). SETTING: Children in the US were selected from 5 managed health plans that used primary care physicians as gatekeepers: 2 health maintenance organizations and 3 point-of-service plans. Point-of-service plans allow patient self-referral at increased out-of-pocket costs. In the UK, the General Practice Research Database provided data from 211 general practices. PARTICIPANTS: Children, from birth to the age of 17 years, with no cost sharing for physician services in the US (n = 135,092) and who were registered with general practitioners, all of whom authorize patients' access to specialty care, in the UK (n = 221,312). MAIN OUTCOME MEASURE: Annual percentage of children referred to a specialist. RESULTS: Across the 5 US plans, 18.6% to 28.8% of the patients per year were referred vs 8.7% of the patients per year in the UK sample. Referral rates were not significantly different between a health maintenance organization and a point-of-service plan administered by a single insurer. Compared with patients in the UK sample, those in the US plans were 1.9 times more commonly referred to medical specialists and 3.2 times more commonly referred to surgical specialists. There was considerable cross-national variation in specialty-specific referral rates for children with selected conditions. CONCLUSIONS: Children in US managed care plans are between 2 and 3 times as likely to be referred to specialists compared with counterparts in the UK. Although these referral rate differences are substantial, our findings cannot be construed to mean that the US referral rates are too high or that the UK rates are too low. The greater supply of specialists and higher expectations for direct access to specialty care in the US, compared with the UK, are likely explanations for these differences in children's specialty referral rates.
Adolescent↗
Prevalence and management of coronary heart disease in primary care: population-based cross-sectional study using a disease register.
BACKGROUND: Patients with coronary heart disease are at high risk of further coronary events. Hence, one of the main priorities in the National Service Framework for Coronary Heart Disease strategy is the identification and treatment of patients with pre-existing coronary heart disease. We aimed to determine the prevalence of established coronary heart disease in a large primary care population and to compare the management of risk factors in these patients with the standards given in the National Service Framework. METHODS: A population-based cross-sectional study was carried out using data collected from primary care. Sixty-three general practices (total list size 378,021) in four primary care groups in SW London took part. Data collection was confined to 103,613 patients over 44 years of age. We calculated age- and sex-specific and age-standardized prevalence rates, and age-adjusted relative risks for men and women. RESULTS: A total of 6,778 patients with coronary heart disease were identified (8 per cent of men and 5 per cent of women over 44 years of age). There was a history of myocardial infarction in 30 per cent (1204/3991) of men and 22 per cent (613/2787) of women (relative risk 1.57; 1.37-1.81). Coronary revascularization procedures had been performed in 27 per cent (1068/3991) of men and 11 per cent (312/2787) of women (2.02; 1.73-2.35). Most patients had been assessed for hypertension (89 per cent (3538/3991) of men; 90 per cent (2500/ 2787) of women), but in many patients blood pressure was poorly controlled (26 per cent (902/3538) of men; 27 per cent (678/2500) of women). Total cholesterol had been recently measured in 51 per cent (2018/3991) of men and 44 per cent (1218/2787) of women and was elevated in 44 per cent (881/ 2018) of men and 59 per cent (716/1218) of women (0.74; 0.69-0.79). Statins were prescribed to 49 per cent (1967/3991) of men and 38 per cent (1064/2787) of women (1.06; 1.00-1.12). Aspirin was prescribed to 65 per cent (2586/3991) of men and 59 per cent (1631/2787) of women (1.08; 1.03-1.14). Beta-blockers were prescribed to 20 per cent (181/913) of men and 15 per cent (72/499) of women with a history of myocardial infarction (1.11; 0.85-1.44). CONCLUSIONS: Most patients with coronary heart disease in primary care were being treated with aspirin but less than half with statins or beta-blockers. More men than women were treated with aspirin and statins, even though women had higher cholesterol levels than men. Men were also more likely to have a confirmed diagnosis and to have undergone a coronary revascularization procedure. There is considerable scope for improving the secondary prevention of coronary heart disease and addressing gender inequalities in primary care.
Aged↗
Workload implications of identifying patients with ischaemic heart disease in primary care: population-based study.
BACKGROUND: The aims of this study were to develop ischaemic heart disease (IHD) registers in three primary care groups (PCGs) in SW London; to determine what proportion of patients with IHD were already identified; and to estimate the workload in producing an IHD disease register. METHODS: A population-based cross-sectional study was carried out in 46 out of 49 general practices in three PCGs in SW London, using computerized and paper medical records. Outcome measures were proportion of patients with IHD on existing disease registers, and workload and cost of producing complete registers. RESULTS: Of 3803 patients with a pre-existing IHD Read code, 570 (15 per cent) were found to have no evidence of IHD, leaving 3233 patients with confirmed or probable IHD. A search of 7726 patients prescribed one of five cardiovascular drugs but not already coded as having IHD identified a further 1447 confirmed or probable cases. On average, coders spent 4.9 hours per 1000 list size verifying IHD cases or finding uncoded cases. Each additional IHD case required about 0.68 hours (41 minutes) of coder's time to identify and one case of IHD was identified or confirmed for about every five sets of notes examined. The cost of each additional case identified was about pounds sterling 10.20. At practice level, there was a wide variation in the proportion of IHD patients already on the register or wrongly coded as having IHD. CONCLUSIONS: A centralized search programme can identify patients with IHD efficiently and at relatively low cost. As the identification of cases is an essential first step in implementing effective secondary prevention, other primary care trusts may also find this method useful in improving the management of patients with IHD.
Aged↗
Comparison of specialty referral rates in the United Kingdom and the United States: retrospective cohort analysis.
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Family Practice↗
Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program.
PURPOSE: We determine the efficacy and tolerability of bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with clinically localized or locally advanced prostate cancer. MATERIALS AND METHODS: This international program consists of 3 ongoing, randomized, double-blind, placebo controlled clinical trials (trials 23, 24, and 25). Men with localized or locally advanced (T1-T4, Nx/N0, M0) prostate cancer were randomized to receive 150 mg. bicalutamide daily or placebo, in addition to standard care with radical prostatectomy, radiotherapy or watchful waiting. Primary end points are time to objective progression and overall survival. In this first analysis data from the trials were combined in a single overview analysis according to protocol. RESULTS: Data are available for 8,113 patients (4,052 randomized to bicalutamide, 4,061 to standard care alone) at a median followup of 3.0 years. Treatment with bicalutamide provided a highly significant reduction of 42% in the risk of objective progression compared with standard care alone (9.0% versus 13.8%, hazards ratio 0.58; 95% confidence interval 0.51, 0.66; p <<0.0001). The overall result was reflected in 2 of the 3 trials (trials 24 and 25) with trial 3 (trial 23) showing a nonsignificant difference at this time. Reductions in the risk of disease progression were seen across the entire patient population, irrespective of primary treatment or disease stage. Overall survival data are currently immature and longer followup will determine if there is also a survival benefit with bicalutamide. The most frequently reported side effects of bicalutamide were gynecomastia and breast pain. CONCLUSIONS: Immediate treatment with 150 mg. bicalutamide daily, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localized or locally advanced prostate cancer. This benefit must be balanced with the morbidity associated with long-term hormonal therapy. Followup is ongoing to determine potential survival benefits of this treatment approach.
Adult↗
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).
BACKGROUND: This placebo-controlled phase III study investigated the effect on survival of gefitinib as second-line or third-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer. METHODS: 1692 patients who were refractory to or intolerant of their latest chemotherapy regimen were randomly assigned in a ratio of two to one either gefitinib (250 mg/day) or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. The primary analysis of the population for survival was by intention to treat. This study has been submitted for registration with ClinicalTrials.gov, number 1839IL/709. FINDINGS: 1129 patients were assigned gefitinib and 563 placebo. At median follow-up of 7.2 months, median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; hazard ratio 0.89 [95% CI 0.77-1.02], p=0.087) or among the 812 patients with adenocarcinoma (6.3 months vs 5.4 months; 0.84 [0.68-1.03], p=0.089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n=375; 0.67 [0.49-0.92], p=0.012; median survival 8.9 vs 6.1 months) and patients of Asian origin (n=342; 0.66 [0.48-0.91], p=0.01; median survival 9.5 vs 5.5 months). Gefitinib was well tolerated, as in previous studies. INTERPRETATION: Treatment with gefitinib was not associated with significant improvement in survival in either coprimary population. There was pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among never-smokers and patients of Asian origin.
Adult↗