Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) ...meta-analysis of these trials was undertaken.
IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed.
Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio HR = 0.86, CI 0.81–0.91; P < 0.00001), as was OS (HR = 0.90, CI 0.85–0.97; P = 0.003). The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. There was no evidence that the benefit of IFN-α differed depending on dose or duration of treatment, or by age, gender, site of primary tumour, disease stage, Breslow thickness, or presence of clinical nodes. Only for ulceration was there evidence of an interaction (test for heterogeneity: P = 0.04 for EFS; P = 0.002 for OS); only patients with ulcerated tumours appeared to obtain benefit from IFN-α.
This meta-analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation.
•Adjuvant IFN-α significantly reduces the risk of relapse and improves overall survival.•There was no evidence of a difference between higher and lower doses of adjuvant IFN-α.•There was no evidence that the benefit of IFN-α differed in different patient types, except for ulceration.•The finding that ulceration may be predictive of response to IFN-α needs confirmation in appropriately designed prospective studies.
To assess the effect of adding interferon-alpha (IFN) +/- interleukin-2 (IL-2) to chemotherapy in patients with metastatic melanoma. METHODS A published data meta-analysis of trials of ...biochemotherapy versus chemotherapy in patients with metastatic melanoma was undertaken. End points evaluated were rates of partial response (PR), complete response (CR) and overall (partial + complete) response (OR); response duration; progression-free survival; overall survival (OS); and toxicity. The only subgroup analysis performed was by type of immunotherapy, with trials divided according to whether IFN only or IFN and IL-2 were administered in the biochemotherapy arm.
Eighteen randomized trials were identified: 11 trials of chemotherapy +/- IFN and seven trials of chemotherapy +/- IFN and IL-2. More than 2,600 patients were entered onto the trials, with 555 responses and 2,039 deaths. There was a clear benefit for biochemotherapy for PR (odds ratio = 0.66; 95% CI, 0.53 to 0.82; P = .0001), CR (odds ratio = 0.50; 95% CI, 0.35 to 0.73; P = .0003) and OR (odds ratio = 0.59; 95% CI, 0.49 to 0.72; P < .00001). For OR, these benefits were significant for both the IFN (odds ratio = 0.60; 95% CI, 0.46 to 0.79; P = .0002) and IFN + IL-2 (odds ratio = 0.58; 95% CI, 0.44 to 0.77; P = .0001) subgroups. In contrast, there was no benefit overall in OS (odds ratio = 0.99; 95% CI, 0.91 to 1.08; P = .9), but there was evidence of heterogeneity of treatment effect between the individual trials (P = .006).
This meta-analysis provides a comprehensive summary of all the data currently available, and shows that although biochemotherapy clearly improves response rates, this does not appear to translate into a survival benefit.
Summary Background Surgical intervention for advanced Parkinson's disease is an option if medical therapy fails to control symptoms adequately. We aimed to assess whether surgery and best medical ...therapy improved self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. Methods The PD SURG trial is an ongoing randomised, open-label trial . At 13 neurosurgical centres in the UK, between November, 2000, and December, 2006, patients with Parkinson's disease that was not adequately controlled by medical therapy were randomly assigned by use of a computerised minimisation procedure to immediate surgery (lesioning or deep brain stimulation at the discretion of the local clinician) and best medical therapy or to best medical therapy alone. Patients were analysed in the treatment group to which they were randomised, irrespective of whether they received their allocated treatment. The primary endpoint was patient self-reported quality of life on the 39-item Parkinson's disease questionnaire (PDQ-39). Changes between baseline and 1 year were compared by use of t tests. This trial is registered with Current Controlled Trials , number ISRCTN34111222. Findings 366 patients were randomly assigned to receive immediate surgery and best medical therapy (183) or best medical therapy alone (183). All patients who had surgery had deep brain stimulation. At 1 year, the mean improvement in PDQ-39 summary index score compared with baseline was 5·0 points in the surgery group and 0·3 points in the medical therapy group (difference −4·7, 95% CI −7·6 to −1·8; p=0·001); the difference in mean change in PDQ-39 score in the mobility domain between the surgery group and the best medical therapy group was −8·9 (95% CI −13·8 to −4·0; p=0·0004), in the activities of daily living domain was −12·4 (−17·3 to −7·5; p<0·0001), and in the bodily discomfort domain was −7·5 (−12·6 to −2·4; p=0·004). Differences between groups in all other domains of the PDQ-39 were not significant. 36 (19%) patients had serious surgery-related adverse events; there were no suicides but there was one procedure-related death. 20 patients in the surgery group and 13 in the best medical therapy group had serious adverse events related to Parkinson's disease and drug treatment. Interpretation At 1 year, surgery and best medical therapy improved patient self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. These differences are clinically meaningful, but surgery is not without risk and targeting of patients most likely to benefit might be warranted. Funding UK Medical Research Council, Parkinson's UK, and UK Department of Health.
Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. The role of physiotherapy is to maximise functional ability and minimise ...secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety and wellbeing, thereby enhancing quality of life. Trials have shown that physiotherapy has short-term benefits in PD. However, which physiotherapy intervention is most effective remains unclear.
To assess the effectiveness of one physiotherapy intervention compared with a second approach in patients with PD.
Relevant trials were identified by electronic searches of numerous literature databases (for example MEDLINE, EMBASE) and trial registers, plus handsearching of major journals, abstract books, conference proceedings and reference lists of retrieved publications. The literature search included trials published up to the end of January 2012.
Randomised controlled trials of one physiotherapy intervention versus another physiotherapy intervention in patients with PD.
Data were abstracted independently from each paper by two authors. Trials were classified into the following intervention comparisons: general physiotherapy, exercise, treadmill training, cueing, dance and martial arts.
A total of 43 trials were identified with 1673 participants. All trials used small patient numbers (average trial size of 39 participants); the methods of randomisation and concealment of allocation were poor or not stated in most trials. Blinded assessors were used in just over half of the trials and only 10 stated that they used intention-to-treat analysis.A wide variety of validated and customised outcome measures were used to assess the effectiveness of physiotherapy interventions. The most frequently reported physiotherapy outcomes were gait speed and timed up and go, in 19 and 15 trials respectively. Only five of the 43 trials reported data on falls (12%). The motor subscales of the Unified Parkinson's Disease Rating Scale and Parkinson's Disease Questionnaire-39 were the most commonly reported clinician-rated disability and patient-rated quality of life outcome measures, used in 22 and 13 trials respectively. The content and delivery of the physiotherapy interventions varied widely in the trials included within this review, so no quantitative meta-analysis could be performed.
Considering the small number of participants examined, the methodological flaws in many of the studies, the possibility of publication bias, and the variety of interventions, formal comparison of the different physiotherapy techniques could not be performed. There is insufficient evidence to support or refute the effectiveness of one physiotherapy intervention over another in PD.This review shows that a wide range of physiotherapy interventions to treat PD have been tested . There is a need for more specific trials with improved treatment strategies to underpin the most appropriate choice of physiotherapy intervention and the outcomes measured.
AbstractObjectiveTo determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease ...relapse.DesignDouble blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis.Setting125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres.Participants237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome.InterventionsChildren were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m2) or a standard eight week course of prednisolone (total dose 2240 mg/m2). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more).Main outcome measuresThe primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat.ResultsNo significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval −0.005 to 0.037) and cost savings (difference −£1673 ($2160; €1930), 95% confidence interval −£3455 to £109).ConclusionsClinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life.Trial registrationISRCTN16645249; EudraCT 2010-022489-29.
ObjectivesTo assess the effects of botulinum toxin for prevention of migraine in adults.DesignSystematic review and meta-analysis.Data sourcesCENTRAL, MEDLINE, Embase and trial registries.Eligibility ...criteriaWe included randomised controlled trials (RCTs) of botulinum toxin compared with placebo, active treatment or clinically relevant different dose for adults with chronic or episodic migraine, with or without the additional diagnosis of medication overuse headache.Data extraction and synthesisCochrane methods were used to review double-blind RCTs. Twelve week post-treatment time-point data was analysed.ResultsTwenty-eight trials (n=4190) were included. Trial quality was mixed. Botulinum toxin treatment resulted in reduced frequency of −2.0 migraine days/month (95% CI −2.8 to −1.1, n=1384) in chronic migraineurs compared with placebo. An improvement was seen in migraine severity, measured on a numerical rating scale 0 to 10 with 10 being maximal pain, of −2.70 cm (95% CI −3.31 to −2.09, n=75) and −4.9 cm (95% CI −6.56 to −3.24, n=32) for chronic and episodic migraine respectively. Botulinum toxin had a relative risk of treatment related adverse events twice that of placebo, but a reduced risk compared with active comparators (relative risk 0.76, 95% CI 0.59 to 0.98) and a low withdrawal rate (3%). Although individual trials reported non-inferiority to oral treatments, insufficient data were available for meta-analysis of effectiveness outcomes.ConclusionsIn chronic migraine, botulinum toxin reduces migraine frequency by 2 days/month and has a favourable safety profile. Inclusion of medication overuse headache does not preclude its effectiveness. Evidence to support or refute efficacy in episodic migraine was not identified.
IntroductionEffective treatments are lacking for idiopathic intracranial hypertension (IIH), a condition characterised by raised intracranial pressure (ICP) and papilloedema, and found primarily in ...obese women. Weight loss and lowering body mass index (BMI) have been shown to lower ICP and improve symptoms in IIH; however, weight loss is typically not maintained, meaning IIH symptoms return. The Idiopathic Intracranial Hypertension Weight Trial (IIH:WT) will assess whether bariatric surgery is an effective long-term treatment for patients with IIH with a BMI over 35 kg/m2. The National Institute for Health and Care Excellence recommends bariatric surgery in people with a BMI over 35 kg/m2 and a qualifying comorbidity; currently IIH does not qualify as a comorbidity.Methods and analysisIIH:WT is a multicentre, open-label, randomised controlled clinical trial of 64 participants with active IIH and a BMI over 35 kg/m2. Participants will be randomised in a 1:1 ratio to bariatric surgery or a dietary weight loss programme and followed up for 5 years. The primary outcome measure is ICP at 12 months. Secondary outcome measures include ICP at 24 and 60 months, and IIH symptoms, visual function, papilloedema, headache, quality of life and cost-effectiveness at 12, 24 and 60 months.Trial registration numberIIH:WT is registered as ISRCTN40152829 and on ClinicalTrials.gov as NCT02124486 and is in the pre-results stage.
The optimal corticosteroid regimen for treating the presenting episode of steroid-sensitive nephrotic syndrome (SSNS) remains uncertain. Most UK centres use an 8-week regimen, despite previous ...systematic reviews indicating that longer regimens reduce the risk of relapse and frequently relapsing nephrotic syndrome (FRNS).
The primary objective was to determine whether or not an extended 16-week course of prednisolone increases the time to first relapse. The secondary objectives were to compare the relapse rate, FRNS and steroid-dependent nephrotic syndrome (SDNS) rates, requirement for alternative immunosuppressive agents and corticosteroid-related adverse events (AEs), including adverse behaviour and costs.
Randomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis.
One hundred and twenty-five UK paediatric departments.
Two hundred and thirty-seven children presenting with a first episode of SSNS. Participants aged between 1 and 15 years were randomised (1 : 1) according to a minimisation algorithm to ensure balance of ethnicity (South Asian, white or other) and age (≤ 5 or ≥ 6 years).
The control group (
= 118) received standard course (SC) prednisolone therapy: 60 mg/m
/day of prednisolone in weeks 1-4, 40 mg/m
of prednisolone on alternate days in weeks 5-8 and matching placebo on alternate days in weeks 9-18 (total 2240 mg/m
). The intervention group (
= 119) received extended course (EC) prednisolone therapy: 60 mg/m
/day of prednisolone in weeks 1-4; started at 60 mg/m
of prednisolone on alternate days in weeks 5-16, tapering by 10 mg/m
every 2 weeks (total 3150 mg/m
).
The primary outcome measure was time to first relapse Albustix
(Siemens Healthcare Limited, Frimley, UK)-positive proteinuria +++ or greater for 3 consecutive days or the presence of generalised oedema plus +++ proteinuria. The secondary outcome measures were relapse rate, incidence of FRNS and SDNS, other immunosuppressive therapy use, rates of serious adverse events (SAEs) and AEs and the incidence of behavioural change using Achenbach Child Behaviour Checklist (ACBC). A comprehensive cost-effectiveness analysis was performed. The analysis was by intention to treat. Participants were followed for a minimum of 24 months.
There was no significant difference in time to first relapse between the SC and EC groups (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log-rank
= 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%;
= 0.7), SDNS (44% vs. 42%;
= 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%;
= 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg (
= 0.07). SAE rates were not significantly different (25% vs. 17%;
= 0.1) and neither were AEs, except poor behaviour (yes/no), which was less frequent with EC treatment. There were no differences in ACBC scores. EC therapy was associated with a mean increase in generic health benefit 0.0162 additional quality-adjusted life-years (QALYs) and cost savings (£4369 vs. £2696).
Study drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating.
This trial has not shown any clinical benefit for EC prednisolone therapy in UK children. The cost-effectiveness analysis suggested that EC therapy may be cheaper, with the possibility of a small QALY benefit.
Studies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted.
Current Controlled Trials ISRCTN16645249 and EudraCT 2010-022489-29.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 23, No. 26. See the NIHR Journals Library website for further project information.
Abstract
Objective
Patients with ANCA-associated vasculitis (AAV) experience high levels of fatigue, despite disease remission. This study assessed the feasibility and acceptability of a definitive ...randomized controlled trial of a behavioural-based physical activity intervention to support fatigue self-management in AAV patients.
Methods
AAV patients in disease remission with fatigue (Multidimensional Fatigue Inventory-20 general fatigue domain ≥14) were randomly allocated to intervention or standard care in this single-centre open-label randomized controlled feasibility study. The intervention lasted 12 weeks and comprised eight face-to-face physical activity sessions with a facilitator and 12 weekly telephone calls. Participants were encouraged to monitor their physical activity using a tracker device (Fitbit). Standard care involved sign-posting to fatigue websites. The primary outcome was feasibility of a phase III trial assessed against three stop/go traffic light criteria, (recruitment, intervention adherence and study withdrawal). A qualitative study assessed participant views about the intervention.
Results
A total of 248 patients were screened and 134 were eligible to participate (54%). Stop/go criteria were amber for recruitment; 43/134 (32%, 95% CI: 24, 40) eligible participants randomized, amber for adherence; 73% of participants attended all eight physical activity sessions, but only 11/22 (50%, 95% CI: 29, 71%) completed the intervention as per the intended schedule, and green for study withdrawal; 2/43 participants withdrew before 24 weeks (5%, 95% CI: 0, 11). Qualitative results suggested the intervention was acceptable.
Conclusion
This study suggests a behavioural-based physical activity intervention targeting fatigue self-management was acceptable to patients with AAV, although recruitment and protocol adherence will need modification prior to a definitive trial.
Clinical Trial Registration Number
ISRCTN11929227.
Dopamine agonists are being used increasingly as first line treatment for Parkinson's disease, but there remains uncertainty about their clinical and cost-effectiveness relative to levodopa.
This ...meta-analysis aims to quantify more reliably the benefits and risks of dopamine agonists compared to placebo or levodopa in early Parkinson's disease.
We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications.
Randomised trials comparing an orally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa in participants with early Parkinson's disease.
Two authors independently extracted data on clinician-rated disability, motor complications, other side-effects, treatment concordance, levodopa dose and mortality.
Twenty-nine eligible trials, involving 5247 participants, were identified. Participants randomised to a dopamine agonist were less likely to develop dyskinesia (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.43 to 0.59; P < 0.00001), dystonia (OR 0.64, 95% CI 0.51 to 0.81; P = 0.0002) and motor fluctuations (OR 0.75, 95% CI 0.63 to 0.90; P = 0.002) than levodopa-treated participants. However, various 'non-motor' side-effects, including oedema (OR 3.68, 95% CI 2.62 to 5.18; P < 0.00001), somnolence (OR 1.49, 95% CI 1.12 to 2.00; P = 0.007), constipation (OR 1.59, 95% CI 1.11 to 2.28; P = 0.01), dizziness (OR 1.45, 95% CI 1.09 to 1.92; P = 0.01), hallucinations (OR 1.69, 95% CI 1.13 to 2.52; P = 0.01) and nausea (OR 1.32, 95% CI 1.05 to 1.66; P = 0.02) were all increased in agonist-treated participants (compared with levodopa-treated participants). Agonist-treated participants were also significantly more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08 to 2.98; P < 0.00001). Finally symptomatic control of Parkinson's disease was better with levodopa than with agonists, but data were reported too inconsistently and incompletely to meta-analyse.
This meta-analysis confirms that motor complications are reduced with dopamine agonists compared to levodopa, but also establishes that other important side-effects are increased and symptom control is poorer with agonists. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared to levodopa.
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