Adjusting for treatment switching in randomised controlled trials - A simulation study and a simplified two-stage method.

Estimates of the overall survival benefit of new cancer treatments are often confounded by treatment switching in randomised controlled trials (RCTs) - whereby patients randomised to the control group are permitted to switch onto the experimental treatment upon disease progression. In health technology assessment, estimates of the unconfounded overall survival benefit associated with the new treatment are needed. Several switching adjustment methods have been advocated in the literature, some of which have been used in health technology assessment. However, it is unclear which methods are likely to produce least bias in realistic RCT-based scenarios. We simulated RCTs in which switching, associated with patient prognosis, was permitted. Treatment effect size and time dependency, switching proportions and disease severity were varied across scenarios. We assessed the performance of alternative adjustment methods based upon bias, coverage and mean squared error, related to the estimation of true restricted mean survival in the absence of switching in the control group. We found that when the treatment effect was not time-dependent, rank preserving structural failure time models (RPSFTM) and iterative parameter estimation methods produced low levels of bias. However, in the presence of a time-dependent treatment effect, these methods produced higher levels of bias, similar to those produced by an inverse probability of censoring weights method. The inverse probability of censoring weights and structural nested models produced high levels of bias when switching proportions exceeded 85%. A simplified two-stage Weibull method produced low bias across all scenarios and provided the treatment switching mechanism is suitable, represents an appropriate adjustment method.

The cost-effectiveness of influenza vaccination of healthy adults 50-64 years of age.

Influenza can cause significant morbidity and mortality. Influenza vaccination is an effective and safe strategy in the prevention of influenza. Currently the National Health Service (NHS) vaccinates 'at-risk' individuals only. This definition includes everyone over 65 years of age but excludes individuals 50-64 years of age unless they have an additional risk factor, such as underlying heart disease or lung disease. In order to examine the cost-effectiveness of an extension of the vaccination policy to include this age group we constructed an economic model to estimate the costs and benefits of vaccination from both a health service and a societal perspective. Data to populate the model was obtained from the literature and the outcome measure used was the quality adjusted life year (QALY). Influenza vaccination prevented an estimated 4508 cases (95% CI: 2431-7606) per 100,000 vaccinees per influenza season for a net cost to the NHS of pound653,221 (95% CI: 354,575-1,072,257). The net cost increased to pound1,139,069 (95% CI 27,052-2,030,473) when non-NHS costs were included and the estimated cost-per-QALY were pound6174 and pound10,766 for NHS and all costs respectively. Extension of the current immunisation policy has the potential to generate a significant health benefit at a comparatively low cost.

A systematic review of molecular and biological markers in tumours of the Ewing's sarcoma family.

The aims of this study were to perform the first systematic review of molecular and biological tumour markers in tumours of the Ewing's sarcoma family (ESFT), and evaluate the current evidence for their clinical use. A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. Papers were independently assessed for tumour markers used in the screening, diagnosis, prognosis or monitoring of patients with ESFT. Eighty-four papers studying the use of 70 different tumour markers in ESFT's were identified. Low-quality, inconsistent reporting limited meta-analysis to that of prognostic data for 28 markers. Patients with tumours lacking S-100 protein expression have a better overall survival (OS) (hazard ratio (HR)=0.41, 95% confidence interval (CI) 0.19, 0.89) than those with expression; patients with high levels of serum LDH had a worse OS and disease-free survival (DFS) (OS: HR=2.92, CI 2.16, 3.94, DFS: HR=3.38, 95% CI 2.28, 4.99); patients with localised disease and tumours expressing type 1 EWS-FLI1 fusion transcripts had an improved DFS compared with those with other fusion transcript types (HR=0.17, 95% CI 0.079, 0.37). The knowledge base formed should facilitate more informative future research. Improved statistical reporting and large, multicentre prospective studies are advocated.