The INTRABEAM® Photon Radiotherapy System for the adjuvant treatment of early breast cancer: a systematic review and economic evaluation.

BACKGROUND: Initial treatment for early breast cancer is usually either breast-conserving surgery (BCS) or mastectomy. After BCS, whole-breast external beam radiotherapy (WB-EBRT) is the standard of care. A potential alternative to post-operative WB-EBRT is intraoperative radiation therapy delivered by the INTRABEAM(®) Photon Radiotherapy System (Carl Zeiss, Oberkochen, Germany) to the tissue adjacent to the resection cavity at the time of surgery. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of INTRABEAM for the adjuvant treatment of early breast cancer during surgical removal of the tumour. DATA SOURCES: Electronic bibliographic databases, including MEDLINE, EMBASE and The Cochrane Library, were searched from inception to March 2014 for English-language articles. Bibliographies of articles, systematic reviews, clinical guidelines and the manufacturer's submission were also searched. The advisory group was contacted to identify additional evidence. METHODS: Systematic reviews of clinical effectiveness, health-related quality of life and cost-effectiveness were conducted. Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to full texts of retrieved papers by one reviewer and checked by a second reviewer. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer, and differences in opinion were resolved through discussion at each stage. Clinical effectiveness studies were included if they were carried out in patients with early operable breast cancer. The intervention was the INTRABEAM system, which was compared with WB-EBRT, and study designs were randomised controlled trials (RCTs). Controlled clinical trials could be considered if data from available RCTs were incomplete (e.g. absence of data on outcomes of interest). A cost-utility decision-analytic model was developed to estimate the costs, benefits and cost-effectiveness of INTRABEAM compared with WB-EBRT for early operable breast cancer. RESULTS: One non-inferiority RCT, TARGeted Intraoperative radioTherapy Alone (TARGIT-A), met the inclusion criteria for the review. The review found that local recurrence was slightly higher following INTRABEAM than WB-EBRT, but the difference did not exceed the 2.5% non-inferiority margin providing INTRABEAM was given at the same time as BCS. Overall survival was similar with both treatments. Statistically significant differences in complications were found for the occurrence of wound seroma requiring more than three aspirations (more frequent in the INTRABEAM group) and for a Radiation Therapy Oncology Group toxicity score of grade 3 or 4 (less frequent in the INTRABEAM group). Cost-effectiveness base-case analysis indicates that INTRABEAM is less expensive but also less effective than WB-EBRT because it is associated with lower total costs but fewer total quality-adjusted life-years gained. However, sensitivity analyses identified four model parameters that can cause a switch in the treatment option that is considered cost-effective. LIMITATIONS: The base-case result from the model is subject to uncertainty because the disease progression parameters are largely drawn from the single available RCT. The RCT median follow-up of 2 years 5 months may be inadequate, particularly as the number of participants with local recurrence is low. The model is particularly sensitive to this parameter. CONCLUSIONS AND IMPLICATIONS: A significant investment in INTRABEAM equipment and staff training (clinical and non-clinical) would be required to make this technology available across the NHS. Longer-term follow-up data from the TARGIT-A trial and analysis of registry data are required as results are currently based on a small number of events and economic modelling results are uncertain. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006720. FUNDING: The National Institute for Health Research Health Technology Assessment programme. Note that the economic model associated with this document is protected by intellectual property rights, which are owned by the University of Southampton. Anyone wishing to modify, adapt, translate, reverse engineer, decompile, dismantle or create derivative work based on the economic model must first seek the agreement of the property owners.

The clinical effectiveness and cost-effectiveness of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C in children and young people: a systematic review and economic evaluation.

BACKGROUND: Optimal therapy for children with chronic hepatitis C is unclear. Two treatment regimens are currently licensed in children. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of peginterferon alfa-2a (Pegasys®, Roche) and peginterferon alfa-2b [ViraferonPeg®, Merck Sharp & Dohme (MSD)] in combination with ribavirin (RBV), within their licensed indications, for the treatment of chronic hepatitis C virus (HCV) in children and young people aged 3-17 years. DATA SOURCES: Twelve electronic bibliographic databases, including The Cochrane Library, MEDLINE and EMBASE, were searched from inception to November 2012. Bibliographies of retrieved papers, key hepatitis C websites and symposia and manufacturers' submissions to the National Institute for Health and Care Excellence were also searched, and clinical experts were contacted. REVIEW METHODS: Systematic reviews of clinical effectiveness and cost-effectiveness were conducted, including studies of health-related quality of life (HRQoL), following standard guidelines to ensure methodological rigour. Clinical effectiveness studies were included if they were in children and young people aged 3-17 years with chronic compensated HCV of any severity, including those with human immunodeficiency virus co-infection and those who were treatment naive or had been previously treated. Eligible interventions were peginterferon alfa-2a or peginterferon alfa-2b, each in combination with RBV, compared against best supportive care (BSC) or against each other, and study designs were randomised controlled trials (RCTs) or non-RCTs, or uncontrolled cohort studies. Outcomes included sustained virological response (SVR) and adverse events. Previously published Markov state-transition economic models of chronic HCV in adults were adapted to estimate the cost-effectiveness of peginterferon alfa-2a and -2b (in combination with RBV), compared with BSC and with one another in children. The model extrapolated the impact of SVR on life expectancy, quality-adjusted life expectancy and lifetime costs. Uncertainty was explored through probabilistic and deterministic sensitivity analyses. RESULTS: Seven studies [two peginterferon alfa-2a and RBV (Copegus®, Roche), and five peginterferon alfa-2b and RBV (Rebetol®, MSD)] were included in the review of clinical effectiveness. Six were single-arm cohort studies and one was a RCT for which only those data for a single arm met the inclusion criteria. Overall, the studies were relatively small and of generally poor quality. SVR rates ranged from 53% to 66% (peginterferon alfa-2a) and 29% to 75% (peginterferon alfa-2b) (49% to 65% if excluding two studies with very small sample sizes). Rates of non-response and relapse were variable and adverse events were generally mild. No studies of cost-effectiveness or HRQoL in children and young people met the inclusion criteria. HRQoL, utilities and costs of treatment were therefore taken from studies of adults with chronic HCV. From this model, peginterferon alfa (-2a or -2b) in combination with RBV was more effective and had lower lifetime costs than BSC. Peginterferon alfa-2a had slightly lower lifetime costs and higher quality-adjusted life-years than peginterferon alfa-2b; therefore, peginterferon alfa-2b was dominated by peginterferon alfa-2a. Results were robust to changes in the sensitivity analyses. LIMITATIONS: There were few good quality studies and parameter data had to be taken from adult studies, which is a limitation of the work. CONCLUSIONS: Treatment of children and young people with peginterferon (alfa-2a or -2b) and RBV may be an effective therapy. Results from the independent Markov model suggest that peginterferon (alfa-2a or -2b) in combination with RBV is cost-effective compared with BSC. However, the available evidence is of poor quality. Future research into the impact of these treatments on growth and quality of life in children and young people is recommended. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002743. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Are trainee teachers being adequately prepared to promote the health and well-being of school children? A survey of current practice.

BACKGROUND: Teachers are a key part of the wider public health workforce in England. We conducted a survey to find out how they are trained for this role during their initial teacher education (ITE). METHODS: Between 2011 and 2012, we sent an online questionnaire to 220 ITE course managers and conducted semi-structured interviews with a purposive sample of 19 course managers to explore issues in more depth. RESULTS: The response rate to the questionnaire was 34% (n = 74). Although most of the course managers felt inclusion of health and well-being training in ITE was important, provision across courses was variable. Topics which are public health priorities [e.g. sex and relationships education (SRE) and drugs, alcohol and tobacco] were covered by fewer courses than other topics (e.g. child protection, emotional health and anti-bullying). Perceived barriers to training included lack of time and a belief that health and well-being were low priorities in educational policy. CONCLUSIONS: Not all of tomorrow's teachers are being adequately prepared for their role in helping to address public health priorities. Educational policy does not appear to be supporting the priorities of public health policy, and this is a key barrier to health promotion training in ITE. Keywords children, educational settings, health promotion.

Shortened peginterferon and ribavirin treatment for chronic hepatitis C.

BACKGROUND: Peginterferon alfa and ribavirin combination therapy is an effective treatment for many patients with chronic hepatitis C virus (HCV). Reducing the length of treatment may be advantageous. We performed a systematic review and economic evaluation to assess shorter treatment duration of this regimen. METHODS: We searched fourteen bibliographic databases (including The Cochrane Library, Medline, and Embase) from 2000 to October 2009 and consulted experts and drug manufacturers. Eligible articles were randomized controlled trials (RCTs) selected according to predefined criteria. We undertook an economic evaluation to assess the cost-effectiveness of shortened treatment versus standard treatment in the UK. RESULTS: Six trials were included. In the sub-group of patients who had low viral load (LVL) and a rapid virological response (RVR), there were no statistically significant differences in sustained virological response (SVR) rates between patients who received standard treatment (range, 83 percent to 100 percent) and those who received shortened courses (range 84 percent to 96 percent) (24 weeks for genotype 1, 16 weeks for genotype 2/3). Shortened treatment resulted in cost savings, but in some scenarios also resulted in poorer outcome, compared with standard treatment. This requires a judgment to be made on the value of the quality-adjusted life-year loss resulting from adopting a shorter treatment regimen, if shorter treatment is associated with a lower SVR than standard treatment duration. CONCLUSIONS: For chronic HCV patients who have LVL and achieve an RVR, shortened peginterferon and ribavirin combination therapy could be considered as a viable treatment option.

An economic model of school-based behavioral interventions to prevent sexually transmitted infections.

OBJECTIVES: Reducing sexually transmitted infections (STI) and teenage pregnancy through effective health education is a high priority for health policy. Behavioral interventions which teach skills to practice safer sex may reduce the incidence of STIs. We evaluated the cost-effectiveness of school-based behavioral interventions in young people. METHODS: We developed an economic model to estimate the total number of STI cases averted, consequent gain in health related quality of life (HRQoL) and savings in medical costs, based on changes in sexual behavior. The parameters for the model were derived from a systematic literature search on the intervention effectiveness, epidemiology of STIs, sexual behavior and lifestyles, HRQoL and health service costs. RESULTS: The costs of providing teacher-led and peer-led behavioral interventions were €5.16 and €18 per pupil, respectively. For a cohort of 1000 boys and 1000 girls aged 15 years, the model estimated that the behavioral interventions would avert two STI cases and save 0.35 Quality Adjusted Life Years (QALYs). Compared to standard education, the incremental cost-effectiveness of the teacher-led and peer-led interventions was €24,268 and €96,938 per QALY gained, respectively. CONCLUSIONS: School-based behavioral interventions which provide information and teach young people sexual health skills can bring about improvements in knowledge and increased self-efficacy, though these may be limited in terms of impact on sexual behavior. There was uncertainty around the results due to the limited effect of the intervention on behavioral outcomes and paucity of data for other input parameters.

Behavioural interventions for the prevention of sexually transmitted infections in young people aged 13-19 years: a systematic review.

We systematically reviewed school-based skills building behavioural interventions for the prevention of sexually transmitted infections. References were sought from 15 electronic resources, bibliographies of systematic reviews/included studies and experts. Two authors independently extracted data and quality-assessed studies. Fifteen randomized controlled trials (RCTs), conducted in the United States, Africa or Europe, met the inclusion criteria. They were heterogeneous in terms of intervention length, content, intensity and providers. Data from 12 RCTs passed quality assessment criteria and provided evidence of positive changes in non-behavioural outcomes (e.g. knowledge and self-efficacy). Intervention effects on behavioural outcomes, such as condom use, were generally limited and did not demonstrate a negative impact (e.g. earlier sexual initiation). Beneficial effect on at least one, but never all behavioural outcomes assessed was reported by about half the studies, but this was sometimes limited to a participant subgroup. Sexual health education for young people is important as it increases knowledge upon which to make decisions about sexual behaviour. However, a number of factors may limit intervention impact on behavioural outcomes. Further research could draw on one of the more effective studies reviewed and could explore the effectiveness of 'booster' sessions as young people move from adolescence to young adulthood.

Topotecan for relapsed small cell lung cancer: a systematic review and economic evaluation.

BACKGROUND: Topotecan is a relatively new drug for use as a second-line treatment in patients with relapsed small cell lung cancer (SCLC). We performed a systematic review and economic evaluation of topotecan, and consider it here in relation to the NICE end of life criteria. METHODS: Seventeen bibliographic databases (including Cochrane library, Medline and Embase) were searched from 1990 to February 2009, and experts and manufacturers were consulted, to identify relevant randomised controlled trials (RCTs) which were selected according to prospectively defined criteria. An economic evaluation was undertaken to assess cost effectiveness compared with best supportive care (BSC) in the UK. RESULTS: Five RCTs were included. The clinical evidence indicates a statistically significant benefit of oral topotecan plus BSC compared to BSC alone for overall survival. Intravenous topotecan was similar in efficacy to both oral topotecan and CAV (cyclophosphamide, doxorubicin and vincristine). In the survival model, oral topotecan plus BSC was associated with an average gain in life expectancy of approximately 4 months, resulting in a gain of 0.183 quality-adjusted life years (QALYs). At an incremental cost of approximately £6200 the incremental cost effectiveness ratio (ICER) is £33,851 per QALY gained. CONCLUSIONS: Compared with BSC alone, oral topotecan for patients with relapsed SCLC was associated with improved health outcomes but at increased cost. The ICER is at the upper extreme of the range conventionally regarded as cost effective from an NHS decision making perspective. However, this treatment may fall under supplementary guidance for life extending, end of life treatments.

Time to full publication of studies of anticancer drugs for breast cancer, and the potential for publication bias.

OBJECTIVES: Nonpublication of results of clinical trials can contribute to inappropriate medical decisions. The primary aim of this systematic review was to investigate publication delays between conference abstracts and full journal publications from randomized controlled trial results of new anticancer agents for breast cancer. The review was restricted to anticancer agents previously, or due to be, appraised in the United Kingdom by the National Institute for Health and Clinical Excellence. A secondary objective was to identify whether there are any apparent biases in the publication and reporting of these trials. METHODS: We searched six electronic databases up to August 2007, including Medline and the Cochrane Library. Two reviewers independently selected studies, extracted and assessed the data. RESULTS: Six anticancer treatments were identified: docetaxel, paclitaxel, trastuzumab, gemcitabine, lapatinib, and bevacizumab. Of eighteen included trials, only four publications from three trials reported the same outcomes in both abstract and full publication. Time delays ranged from 5 to 19 months. Eleven trial abstracts were still without a full publication at the end of our searches, varying from 3 to 38 months since abstract publication. Observational analysis revealed no particular publishing biases. CONCLUSIONS: Whereas delays in publication appear reasonable over a period of months, many were not published in full over a period of years and others would appear to be unlikely to ever be published. Further research should investigate the impact of publication delays on the availability of new drug treatments in clinical practice.

Pegylated and non-pegylated interferon-alfa and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and meta-analysis.

OBJECTIVES: Traditionally, patients with chronic hepatitis C virus (HCV) infection have not received treatment until their infection reaches the moderate to severe stage. The aim of this systematic review was to assess the clinical effectiveness of pegylated (PEG) and non-pegylated interferon (IFN) alfa and ribavirin (RBV) for the treatment of adults with histologically mild HCV. METHODS: We performed a sensitive search of fourteen electronic bibliographic databases for literature that met criteria defined in a research protocol. Two reviewers independently selected studies, extracted data and assessed methodological quality. RESULTS: Ten randomized, controlled trials (RCTs) were included. Treatment with PEG + RBV combination therapy resulted in significantly higher sustained virological response (SVR) rates than treatment with IFN + RBV combination therapy. Treatment for 48 weeks with PEG + RBV was significantly more effective than the same treatment for 24 weeks. Significantly higher SVR rates were seen with IFN + RBV compared with either IFN monotherapy or no treatment. In the meta-analysis (four IFN trials), the relative risk of not experiencing an SVR was 0.59 (95 percent CI, 0.51 - 0.69) and was statistically significant (p < .00001). SVRs were higher for patients with genotype non-1 compared with genotype 1 for both PEG + RBV and IFN + RBV treatments. CONCLUSIONS: Patients with histologically mild HCV can be successfully treated with both PEG and IFN combination therapy, and response rates are broadly comparable with those achieved in patients with advanced disease. Treating patients in the early milder stages of HCV is, therefore, a clinically effective option.

Dietary advice for patients undergoing coronary artery bypass surgery: falling on deaf ears?

Coronary heart disease (CHD) is the most common cause of death in the UK, accounting for around 125,000 deaths per year. Diet is a CHD risk factor that is modifiable, and therefore has the potential to alter the risk for CHD. At present, little is known about the dietary patterns of CHD patients. The present study aimed to assess the effectiveness of dietary advice administered to patients undergoing coronary artery bypass grafting (CABG) surgery. Dietary intake was assessed on three occasions (pre-operatively, 2 months after surgery and 1 year after surgery) by use of a food amount frequency questionnaire that had been previously validated. Patients were also asked to provide information on any dietary advice they had received. Complete data were available for 15 males, aged 51-79 years, who were admitted for CABG surgery. The absolute mean intakes of total fat, saturated fat and dietary cholesterol significantly increased 1 year after CABG surgery by 21%, 36% and 51%, respectively, and the choice of food items reflected this change in nutrient intake. These undesirable changes occurred despite the provision of dietary advice. This may consequently increase the risk of recurrent problems, and serve to promote further atherosclerosis in the arteries of such patients. The observations highlight the need to better understand the barriers to nutritional advice and compliance seen in CABG patients.