A Systematic Review of the Efficacy and Toxicity of Brachytherapy Boost Combined with External Beam Radiotherapy for Nonmetastatic Prostate Cancer.

CONTEXT: The optimum use of brachytherapy (BT) combined with external beam radiotherapy (EBRT) for localised/locally advanced prostate cancer (PCa) remains uncertain. OBJECTIVE: To perform a systematic review to determine the benefits and harms of EBRT-BT. EVIDENCE ACQUISITION: Ovid MEDLINE, Embase, and EBM Reviews-Cochrane Central Register of Controlled Trials databases were systematically searched for studies published between January 1, 2000 and June 7, 2022, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Eligible studies compared low- or high-dose-rate EBRT-BT against EBRT ± androgen deprivation therapy (ADT) and/or radical prostatectomy (RP) ± postoperative radiotherapy (RP ± EBRT). The main outcomes were biochemical progression-free survival (bPFS), severe late genitourinary (GU)/gastrointestinal toxicity, metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS), at/beyond 5 yr. Risk of bias was assessed and confounding assessment was performed. A meta-analysis was performed for randomised controlled trials (RCTs). EVIDENCE SYNTHESIS: Seventy-three studies were included (two RCTs, seven prospective studies, and 64 retrospective studies). Most studies included participants with intermediate-or high-risk PCa. Most studies, including both RCTs, used ADT with EBRT-BT. Generally, EBRT-BT was associated with improved bPFS compared with EBRT, but similar MFS, CSS, and OS. A meta-analysis of the two RCTs showed superior bPFS with EBRT-BT (estimated fixed-effect hazard ratio [HR] 0.54 [95% confidence interval {CI} 0.40-0.72], p < 0.001), with absolute improvements in bPFS at 5-6 yr of 4.9-16%. However, no difference was seen for MFS (HR 0.84 [95% CI 0.53-1.28], p = 0.4) or OS (HR 0.87 [95% CI 0.63-1.19], p = 0.4). Fewer studies examined RP ± EBRT. There is an increased risk of severe late GU toxicity, especially with low-dose-rate EBRT-BT, with some evidence of increased prevalence of severe GU toxicity at 5-6 yr of 6.4-7% across the two RCTs. CONCLUSIONS: EBRT-BT can be considered for unfavourable intermediate/high-risk localised/locally advanced PCa in patients with good urinary function, although the strength of this recommendation based on the European Association of Urology guideline methodology is weak given that it is based on improvements in biochemical control. PATIENT SUMMARY: We found good evidence that radiotherapy combined with brachytherapy keeps prostate cancer controlled for longer, but it could lead to worse urinary side effects than radiotherapy without brachytherapy, and its impact on cancer spread and patient survival is less clear.

Developing a topic-based repository of clinical trial individual patient data: experiences and lessons learned from a pilot project.

BACKGROUND: Building a dataset of individual participant data (IPD) for meta-analysis represents considerable research investment as well as collaboration across multiple institutions and researchers. Making arrangements to curate and share the dataset beyond the IPD meta-analysis project for which it was established, for reuse in future research projects, would maximise the value of this investment. METHODS: Our aim was to establish the Cochrane repository for individual patient data from clinical trials in pregnancy and childbirth (CRIB) as an example of how an IPD repository could become part of Cochrane infrastructure. We believed that establishing CRIB under Cochrane auspices would engender trust and encourage trial investigators to share data, and at the same time position Cochrane to take steps towards expanding the number of reviews with IPD synthesis. RESULTS: CRIB was designed as a web-based platform to receive, host and facilitate onward sharing of de-identified data. Development was not straightforward and we did not fully achieve our aim as intended. We describe the challenges encountered and suggest ways that future repositories might overcome these. In particular, securing the legal agreements required to facilitate data sharing proved to be the main barrier, being time-consuming and more complex than anticipated. CONCLUSIONS: We would recommend that researchers conducting IPD meta-analysis should consider discussing the option to transfer the curated IPD datasets to a repository at the end of the initial meta-analysis and this should be recognised within the data sharing agreements made with the original data contributors.

Determining the effectiveness of fibrin sealants in reducing complications in patients undergoing lateral neck dissection (DEFeND): study protocol for a randomised external pilot trial.

BACKGROUND: Complications after major surgery are a significant cause of morbidity and mortality. Neck dissection is one of the most commonly performed major operations in Head and Neck Surgical Oncology. Significant surgical complications occur in approximately 10-20% of all patients, increasing to 40% in patients who have had previous treatment to the area or have multiple co-morbidities and/or polypharmacy.Current evidence suggests that fibrin sealants (FS) may have potential clinical advantages in Head and Neck Surgery through the reduction of complications, volume of wound drainage and retention time of the drains. However, a paucity of high-quality trial-based evidence means that a surgical trial to determine the effectiveness of FS in reducing the rate and severity of complications in patients undergoing lateral neck dissection is warranted. The DEFeND randomised external pilot trial will address critical questions on how well key components of the proposed study design work together as well as the feasibility of a future phase III trial. METHODS: The study design that is being piloted is that of a two-arm, parallel group, superiority trial with block randomisation in a 1:1 allocation ratio. The interventional arm will constitute the application of FS (Artiss, Baxter Healthcare Ltd.) to the surgical wound following completion of a neck dissection procedure, in addition to standard of care (SOC). The control arm will constitute SOC alone. Eligible patients will include patients who require a lateral neck dissection with a minimum of three cervical nodal levels. Patients who require bilateral neck procedures or undergoing immediate reconstruction with free or regional flaps will be excluded. The outcomes being assessed will be recruitment rate, screened to randomisation rate, fidelity of blinding process using blinding indices, number of missing or incomplete data entries, number of protocol deviations and number of losses to follow-up. Suitability of the outcome measures proposed for the future phase III trial will also be assessed. DISCUSSION: The anticipated challenges for this study will be recruitment, complexity of the intervention and adherence to the protocol. The outcomes will inform the design, feasibility and conduct of a future phase III surgical trial. TRIAL REGISTRATION: First participant randomised: November 06, 2018; UKCRN Portfolio ID: 37896; ISRCTN99181100.

A guide on meta-analysis of time-to-event outcomes using aggregate data in vascular and endovascular surgery.

BACKGROUND: Time-to-event outcomes measure not only whether but also when an event happens. They are commonly used to evaluate vascular therapies, where the events of interest include disease recurrence (eg, loss of graft patency), reintervention (eg, target lesion revascularization), or death. Meta-analyses of published time-to-event outcomes are most appropriately measured by hazard ratios (HR). METHODS: We constructed a guide to increase awareness and adoption of these methods in vascular and endovascular surgery research, make systematic reviewers familiar with the basic principles of time-to-event data meta-analysis, and provide information about useful resources. RESULTS: Commonly, values of HR are not provided in published studies, but there are methods available to obtain such values and associated statistics from published summary data. Both direct and indirect methods can be applied to calculate the HR and its variance or standard error. Once individual study estimates of HR and its variance (or standard error) have been obtained, a pooled estimate of the log HR and variance can be calculated using the inverse-variance method. CONCLUSIONS: Time-to-event data should not be analyzed as dichotomous data. Such meta-analyses need to account for time and the differential censoring of the subjects. The HR is the preferred treatment effect measure. A mixture of direct or indirect methods can be applied to calculate the individual study estimates.

Individualised prediction of psychosis in individuals meeting at-risk mental state (ARMS) criteria: protocol for a systematic review of clinical prediction models.

BACKGROUND: Psychotic disorders affect about 3% of the population worldwide and are associated with high personal, social and economic costs. They tend to have their first onset in adolescence. Increasing emphasis has been placed on early intervention to detect illness and minimise disability. In the late 1990s, criteria were developed to identify individuals at high risk for psychotic disorder. These are known as the at-risk mental state (ARMS) criteria. While ARMS individuals have a risk of psychosis much greater than the general population, most individuals meeting the ARMS criteria will not develop psychosis. Despite this, the National Institute for Health and Care Excellence recommends cognitive behavioural therapy (CBT) for all ARMS people.Clinical prediction models that combine multiple patient characteristics to predict individual outcome risk may facilitate identification of patients who would benefit from CBT and conversely those that would benefit from less costly and less intensive regular mental state monitoring. The study will systematically review the evidence on clinical prediction models aimed at making individualised predictions for the transition to psychosis. METHODS: Database searches will be conducted on PsycINFO, Medline, EMBASE and CINAHL. Reference lists and subject experts will be utilised. No language restrictions will be placed on publications, but searches will be restricted to 1994 onwards, the initial year of the first prospective study using ARMS criteria. Studies of any design will be included if they examined, in ARMS patients, whether more than one factor in combination is associated with the risk of transition to psychosis. Study quality will be assessed using the prediction model risk of bias assessment tool (PROBAST). Clinical prediction models will be summarised qualitatively, and if tested in multiple validation studies, their predictive performance will be summarised using a random-effects meta-analysis model. DISCUSSION: The results of the review will identify prediction models for the risk of transition to psychosis. These will be informative for clinicians currently treating ARMS patients and considering potential preventive interventions. The conclusions of the review will also inform the possible update and external validation of prediction models and clinical prediction rules to identify those at high or low risk of transition to psychosis. TRIAL REGISTRATION: The review has been registered with PROSPERO (CRD42018108488).

The efficacy of interventions for test-anxious university students: A meta-analysis of randomized controlled trials.

Test anxiety (TA) is highly distressing and can significantly undermine academic performance. Many randomized controlled trials (RCTs) of interventions for university students with TA have been conducted, but there has been no systematic review of their efficacy. This meta-analysis examines the efficacy of interventions for test-anxious university students in: (i) reducing TA, and (ii) improving academic performance. We searched for RCTs published in English language peer-reviewed journals. Forty-four RCTs met our eligibility criteria (n = 2,209). Interventions were superior to control conditions at post-treatment for reducing TA (g = -0.76) and improving academic performance (g = 0.37). Interventions were superior to control conditions at follow-up. Subgroups analyses found most support for behaviour therapy. Cognitive-behavioural therapy, study skills training, and combined psychological and study skills training interventions show promise but lack evidence for their longer-term efficacy, and results are based upon a small number of studies. Evidence of publication bias was found and poor quality of reporting meant that confidence in results should be moderated. Future RCTs should be conducted and reported with greater rigour, have larger samples, and examine newer interventions.

Exploring changes over time and characteristics associated with data retrieval across individual participant data meta-analyses: systematic review.

Objective To investigate whether the success rate of retrieving individual participant data (IPD) for use in IPD meta-analyses has increased over time, and to explore the characteristics associated with IPD retrieval.Design Systematic review of published IPD meta-analyses, supplemented by a reflection of the Cochrane Epilepsy Group's 20 years' experience of requesting IPD.Data sources Medline, CENTRAL, Scopus, Web of Science, CINAHL Plus, and PsycINFO.Eligibility criteria for study selection IPD meta-analyses of studies of all designs and all clinical areas published in English.Results 760 IPD meta-analyses which identified studies by systematic methods that had been published between 1987 and 2015 were included. Only 188 (25%) of these IPD meta-analyses retrieved 100% of the eligible IPD for analysis, with 324 (43%) of these IPD meta-analyses retrieving 80% or more of relevant IPD. There is insufficient evidence to suggest that IPD retrieval rates have improved over time. IPD meta-analyses that included only randomised trials, had an authorship policy, included fewer eligible participants, and were conducted outside of the Cochrane Database of Systematic Reviews were associated with a high or complete IPD retrieval rate. There was no association between the source of funding of the IPD meta-analyses and IPD retrieval rate. The IPD retrieval rate of the Cochrane Epilepsy Group has declined from 83% (up to 2005) to 65% (between 2012 and 2015) and the reported reasons for lack of data availability have changed in recent years.Conclusions IPD meta-analyses are considered to be the "gold standard" for the synthesis of data from clinical research studies; however, only 25% of published IPD meta-analyses have had access to all IPD.

Reporting of harms outcomes: a comparison of journal publications with unpublished clinical study reports of orlistat trials.

BACKGROUND: The quality of harms reporting in journal publications is often poor, which can impede the risk-benefit interpretation of a clinical trial. Clinical study reports can provide more reliable, complete, and informative data on harms compared to the corresponding journal publication. This case study compares the quality and quantity of harms data reported in journal publications and clinical study reports of orlistat trials. METHODS: Publications related to clinical trials of orlistat were identified through comprehensive literature searches. A request was made to Roche (Genentech; South San Francisco, CA, USA) for clinical study reports related to the orlistat trials identified in our search. We compared adverse events, serious adverse events, and the reporting of 15 harms criteria in both document types and compared meta-analytic results using data from the clinical study reports against the journal publications. RESULTS: Five journal publications with matching clinical study reports were available for five independent clinical trials. Journal publications did not always report the complete list of identified adverse events and serious adverse events. We found some differences in the magnitude of the pooled risk difference between both document types with a statistically significant risk difference for three adverse events and two serious adverse events using data reported in the clinical study reports; these events were of mild intensity and unrelated to the orlistat. The CONSORT harms reporting criteria were often satisfied in the methods section of the clinical study reports (70-90 % of the methods section criteria satisfied in the clinical study reports compared to 10-50 % in the journal publications), but both document types satisfied 80-100 % of the results section criteria, albeit with greater detail being provided in the clinical study reports. CONCLUSIONS: In this case study, journal publications provided insufficient information on harms outcomes of clinical trials and did not specify that a subset of harms data were being presented. Clinical study reports often present data on harms, including serious adverse events, which are not reported or mentioned in the journal publications. Therefore, clinical study reports could support a more complete, accurate, and reliable investigation, and researchers undertaking evidence synthesis of harm outcomes should not rely only on incomplete published data that are presented in the journal publications.

Individual Participant Data (IPD) Meta-analyses of Randomised Controlled Trials: Guidance on Their Use.

Jayne Tierney and colleagues offer guidance on how to spot a well-designed and well-conducted individual participant data meta-analysis.

Interventions to improve recruitment and retention in clinical trials: a survey and workshop to assess current practice and future priorities.

BACKGROUND: Despite significant investment in infrastructure many trials continue to face challenges in recruitment and retention. We argue that insufficient focus has been placed on the development and testing of recruitment and retention interventions. METHODS: In this current paper, we summarize existing reviews about interventions to improve recruitment and retention. We report survey data from Clinical Trials Units in the United Kingdom to indicate the range of interventions used by these units to encourage recruitment and retention. We present the views of participants in a recent workshop and a priority list of recruitment interventions for evaluation (determined by voting among workshop participants). We also discuss wider issues concerning the testing of recruitment interventions. RESULTS: Methods used to encourage recruitment and retention were categorized as: patient contact, patient convenience, support for recruiters, monitoring and systems, incentives, design, resources, and human factors. Interventions felt to merit investigation by respondents fell into three categories: training site staff, communication with patients, and incentives. CONCLUSIONS: Significant resources continue to be invested into clinical trials and other high quality studies, but recruitment remains a significant challenge. Adoption of innovative methods to develop, test, and implement recruitment interventions are required.

External validation of a prognostic model for seizure recurrence following a first unprovoked seizure and implications for driving.

OBJECTIVE: In the United Kingdom and other European Union countries guidelines for driving following a first unprovoked seizure require the risk of another seizure in the next year to be less than 20%. Using data from one clinical trial, we previously developed a prognostic model to inform driving guidelines. The objective of this work is to externally validate our published model and demonstrate its generalisability. METHODS: A cohort of 620 people with a first unprovoked seizure was used to develop the original model which included variables for aetiology, first degree relative with epilepsy, seizures only while asleep, electroencephalogram, computed tomography or magnetic resonance scan result, and treatment policy. The validation cohorts consisted of 274 (United Kingdom), 305 (Italy), and 847 (Australia) people. The model was evaluated using discrimination and calibration methods. A covariate, missing from the Italian dataset, was handled via five imputation methods. Following external validation, the model was fitted to a pooled population comprising all validation datasets and the development dataset. The model was stratified by dataset. RESULTS: The model generalised relatively well. All methods of imputation performed fairly similarly. At six months, the risk of a seizure recurrence following a first ever seizure, based on the pooled datasets, is 15% (95% CI: (12% to 18%)) for patients who are treated immediately and 18% (95% CI: (15 to 21%)) otherwise. Individuals can be reliably stratified into risk groups according to the clinical factors included in the model. SIGNIFICANCE: Our prognostic model, used to inform driving regulations, has been validated and consequently has been proven as a valuable tool for predicting risk of seizure recurrence following a first seizure in people with various combinations of risk factors. Additionally, there is evidence to support one worldwide overall prognostic model for risk of second seizure following a first.

Patient-level compared with study-level meta-analyses demonstrate consistency of D-dimer as predictor of venous thromboembolic recurrences.

OBJECTIVE: We compared the performance of aggregate data (AD)--based and individual patient data (IPD)-based meta-analyses to synthesize evidence on the ability of D-dimer to distinguish recurrence risk in patients with unprovoked venous thromboembolism (VTE) who stopped anticoagulation. STUDY DESIGN AND SETTING: We compared the results of the published AD-based rate ratio of VTE recurrence for positive vs. negative D-dimer, estimated by a mixed-effect Poisson model, with those of the IPD-based hazard ratio obtained by a Cox regression stratified by trial. We performed three additional analyses to investigate the methodological reasons for differences between the two approaches, comparing the IPD Cox regression with AD generated from IPD Poisson regression (to control for differences in population on study), AD time-to-event meta-analysis, and AD generated from IPD meta-regression. RESULTS: Published analyses agreed in direction and statistical significance when estimating the prognostic value of D-dimer even if IPD estimates suggested a stronger effect. The additional analyses suggested that differences in study populations might explain this slight difference. Poor reporting in published studies precluded a true comparison of AD- and IPD-based assessments of heterogeneity sources. CONCLUSION: AD and IPD meta-analyses yielded similar estimates of D-dimer effect to distinguish risk for recurrent VTE. The IPD approach was justified by the need to investigate sources of heterogeneity.

Combining individual patient data and aggregate data in mixed treatment comparison meta-analysis: Individual patient data may be beneficial if only for a subset of trials.

BACKGROUND: Individual patient data (IPD) meta-analysis is the gold standard. Aggregate data (AD) and IPD can be combined using conventional pairwise meta-analysis when IPD cannot be obtained for all relevant studies. We extend the methodology to combine IPD and AD in a mixed treatment comparison (MTC) meta-analysis. METHODS: The proposed random-effects MTC models combine IPD and AD for a dichotomous outcome. We study the benefits of acquiring IPD for a subset of trials when assessing the underlying consistency assumption by including treatment-by-covariate interactions in the model. We describe three different model specifications that make increasingly stronger assumptions regarding the interactions. We illustrate the methodology through application to real data sets to compare drugs for treating malaria by using the outcome unadjusted treatment success at day 28. We compare results from AD alone, IPD alone and all data. RESULTS: When IPD contributed (i.e. either using IPD alone or combining IPD and AD), the chains converged, and we identified statistically significant regression coefficients for the interactions. Using IPD alone, we were able to compare only three of the six treatments of interest. When models were fitted to AD, the treatment effects and regression coefficients for the interactions were far more imprecise, and the chains did not converge. CONCLUSIONS: The models combining IPD and AD encapsulated all available evidence. When exploring interactions, it can be beneficial to obtain IPD for a subset of trials and to combine IPD with additional AD.

Prognostic factors for time to treatment failure and time to 12 months of remission for patients with focal epilepsy: post-hoc, subgroup analyses of data from the SANAD trial.

BACKGROUND: Epilepsy is a heterogeneous disorder, with outcomes ranging from immediate remission after taking a first antiepileptic drug to frequent unremitting seizures with multiple treatment failures. Few prognostic models enable prediction of outcome; we therefore aimed to use data from the SANAD study to predict outcome overall and for patients receiving specific treatments. METHODS: The SANAD study was a randomised controlled trial in which standard antiepileptic drugs were compared with new treatments. Arm A included patients for whom carbamazepine was considered the first-line treatment, most of whom were newly diagnosed with focal epilepsy. Patients were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Outcomes were time to treatment failure overall, because of inadequate seizure control, and because of adverse events, and time to 12 months of remission from seizures. In this post-hoc study we used regression multivariable modelling to investigate how clinical factors affect the probability of treatment failure and the probability of achieving 12 months of remission. FINDINGS: For time to treatment failure, we identified several significant risk factors: sex (male vs female, hazard ratio [HR] 0·86, 95% CI 0·75-0·99), treatment history (taking non-SANAD antiepileptic drugs [other than those listed above] vs treatment naive, 1·27, 1·05-1·53), age (eg, older than 71 years vs 10 years or younger, 0·68, 0·51-0·91), total number of seizures (eg, four to 11 seizures vs two or fewer, 1·08, 1·05-1·11), electroencephalogram results (epileptiform abnormality vs normal, 1·26, 1·07-1·50), seizure type (eg, secondary generalised vs simple or complex partial only, 0·78, 0·66-0·91), site of onset (not localised vs temporal lobe, 1·25, 1·06-1·47), and treatment (lamotrigine vs carbamazepine, 0·76, 0·61-0·95). Significant factors for time to 12 months of remission were sex (male vs female, 1·19, 1·05-1·35), treatment history (taking a non-SANAD antiepileptic drug vs treatment naive, 0·64, 0·52-0·78), age (eg, older than 71 years vs 10 years or younger, 1·60, 1·26-2·03), time from first seizure (60-239 months vs ≥2 months, 1·14, 1·01-1·29; >240 months vs ≤2 months, 1·39, 1·04-1·86), neurological insult (present vs absent, 0·75, 0·61-0·93), total number of seizures before randomisation (eg, four to 11 vs two or fewer, 0·87, 0·85-0·90), and treatment (gabapentin vs carbamazepine, 0·71, 0·59-0·86; topiramate vs carbamazepine, 0·81, 0·68-0·98). INTERPRETATION: We present a thorough investigation of prognostic factors from a large randomised controlled trial in patients starting antiepileptic monotherapy. If validated, our models could aid in individual patient risk stratification and the design and analysis of epilepsy trials. FUNDING: National Institute for Health Research (UK).

Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I(131) KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma.

BACKGROUND: Advanced pancreatic cancer has a poor prognosis, and the current standard of care (gemcitabine based chemotherapy) provides a small survival advantage. However the drawback is the accompanying systemic toxicity, which targeted treatments may overcome. This study aimed to evaluate the safety and tolerability of KAb201, an anti-carcinoembryonic antigen monoclonal antibody, labelled with I(131) in pancreatic cancer (ISRCTN 16857581). METHODS: Patients with histological/cytological proven inoperable adenocarcinoma of the head of pancreas were randomised to receive KAb 201 via either the intra-arterial or intravenous delivery route. The dose limiting toxicities within each group were determined. Patients were assessed for safety and efficacy and followed up until death. RESULTS: Between February 2003 and July 2005, 25 patients were enrolled. Nineteen patients were randomised, 9 to the intravenous and 10 to the intra-arterial arms. In the intra-arterial arm, dose limiting toxicity was seen in 2/6 (33%) patients at 50 mCi whereas in the intravenous arm, dose limiting toxicity was noted in 1/6 patients at 50 mCi, but did not occur at 75 mCi (0/3).The overall response rate was 6% (1/18). Median overall survival was 5.2 months (95% confidence interval = 3.3 to 9 months), with no significant difference between the intravenous and intra-arterial arms (log rank test p = 0.79). One patient was still alive at the time of this analysis. CONCLUSION: Dose limiting toxicity for KAb201 with I(131) by the intra-arterial route was 50 mCi, while dose limiting toxicity was not reached in the intravenous arm.

Gemcitabine based combination chemotherapy in advanced pancreatic cancer-indirect comparison.

BACKGROUND: Recent meta-analyses have found a survival advantage with gemcitabine based combinations over single agent gemcitabine in patients with advanced pancreatic cancer. There is paucity of evidence in the form of direct head-to-head randomised controlled trials to determine which combinations are to be preferred. METHOD: Using the adjusted indirect comparison method proposed by Bucher et al, we have assessed randomised controlled trials of four gemcitabine based combinations namely gemcitabine plus a platinum compound or 5-fluorouracil or irinotecan or capecitabine. RESULTS: No particular combination was significantly superior to another, but the indirect evidence suggests some important trends. CONCLUSION: The strongest trends on indirect comparison are towards favouring gemcitabine plus capecitabine or gemcitabine plus a platinum compound over gemcitabine plus irinotecan, and to a lesser degree, over gemcitabine plus 5-fluorouracil.

Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer.

PURPOSE: There are a large number of randomized controlled trials involving chemotherapy in the management of advanced pancreatic cancer. Several chemotherapeutic agents, either alone or in combination with other chemotherapy or novel agents, have been used. The aim of these meta-analyses was to examine the different therapeutic approaches, and the comparisons examined were as follows: chemotherapy versus best supportive care; fluorouracil (FU) versus FU combination chemotherapy; gemcitabine versus FU; and gemcitabine versus gemcitabine combination chemotherapy. METHODS: Relevant trials were identified by searching databases, trial registers, and conference proceedings. The primary end point was overall survival. RESULTS: One hundred thirteen randomized controlled trials were identified, of which 51 trials involving 9,970 patients met the inclusion criteria. Chemotherapy improved survival compared with best supportive care (hazard ratio [HR] = 0.64; 95% CI, 0.42 to 0.98). FU-based combination chemotherapy did not result in better overall survival compared with FU alone (HR = 0.94; 95% CI, 0.82 to 1.08). There was insufficient evidence of a survival difference between gemcitabine and FU, but the wide CI includes clinically important differences in both directions, making a clear conclusion difficult (HR = 0.75; 95% CI, 0.42 to 1.31). Survival was improved after gemcitabine combination chemotherapy compared with gemcitabine alone (HR = 0.91; 95% CI, 0.85 to 0.97). CONCLUSION: There was a significant survival benefit for chemotherapy over best supportive care and gemcitabine combinations over gemcitabine alone. This supports the use of gemcitabine-based combination chemotherapy in the treatment of advanced pancreatic cancer.

The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.

BACKGROUND: Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes. METHODS: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS: For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0.78 [95% CI 0.63-0.97]), gabapentin (0.65 [0.52-0.80]), and topiramate (0.64 [0.52-0.79]), and had a non-significant advantage compared with oxcarbazepine (1.15 [0.86-1.54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0.75 [0.63-0.90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0.91 [0.77-1.09]), topiramate (0.86 [0.72-1.03]), and oxcarbazepine (0.92 [0.73-1.18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (-8 to 7) and 5 (-3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine. INTERPRETATION: Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures.

The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.

BACKGROUND: Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. METHODS: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS: For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1.57 [95% CI 1.19-2.08]), but there was no significant difference between valproate and lamotrigine (1.25 [0.94-1.68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1.55 [1.07-2.24] and topiramate (1.89 [1.32-2.70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0.76 [0.62-0.94]), and for the subgroup with an idiopathic generalised epilepsy 0.68 (0.53-0.89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. INTERPRETATION: Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

Importance of competing risks in the analysis of anti-epileptic drug failure.

BACKGROUND: Retention time (time to treatment failure) is a commonly used outcome in antiepileptic drug (AED) studies. METHODS: Two datasets are used to demonstrate the issues in a competing risks analysis of AEDs. First, data collection and follow-up considerations are discussed with reference to information from 15 monotherapy trials. Recommendations for improved data collection and cumulative incidence analysis are then illustrated using the SANAD trial dataset. The results are compared to the more common approach using standard survival analysis methods. RESULTS: A non-significant difference in overall treatment failure time between gabapentin and topiramate (logrank test statistic = 0.01, 1 degree of freedom, p-value = 0.91) masked highly significant differences in opposite directions with gabapentin resulting in fewer withdrawals due to side effects (Gray's test statistic = 11.60, 1 degree of freedom, p = 0.0007) but more due to poor seizure control (Gray's test statistic = 14.47, 1 degree of freedom, p-value = 0.0001). The significant difference in overall treatment failure time between lamotrigine and carbamazepine (logrank test statistic = 5.6, 1 degree of freedom, p-value = 0.018) was due entirely to a significant benefit of lamotrigine in terms of side effects (Gray's test statistic = 10.27, 1 degree of freedom, p = 0.001). CONCLUSION: Treatment failure time can be measured reliably but care is needed to collect sufficient information on reasons for drug withdrawal to allow a competing risks analysis. Important differences between the profiles of AEDs may be missed unless appropriate statistical methods are used to fully investigate treatment failure time. Cumulative incidence analysis allows comparison of the probability of failure between two AEDs and is likely to be a more powerful approach than logrank analysis for most comparisons of standard and new anti-epileptic drugs.