Title: Antiemetic medications for the prevention and treatment of chemotherapy-induced nausea and vomiting in children and young people. A systematic review and Bayesian network meta-analysis with methods for extrapolation of adult clinical trial information.
Funder: Department of Health and Social Care

Abstract: BackgroundChemotherapy-induced nausea and vomiting (CINV) continues to be a problem for children and young people, despite the development of new antiemetic medications. Most research investigating the use of these agents has been conducted in adults, and much less is known about the relative effectiveness of these therapies in children. This has led to inconsistencies in prescribing and means that new and potentially more effective treatments are usually licenced in adults, many years before children have access to the same therapy.Aims To overcome this scarcity of evidence in the paediatric population, this research aims to synthesise evidence of effectiveness from clinical trials comparing pharmacological interventions for the prevention of CINV in children and young people; and where evidence is lacking, determine whether adult clinical trial data can be incorporated to make inferences about the effectiveness of these medications in the paediatric population.Methods I will apply systematic review and Bayesian network meta-analysis (NMA) to estimate the relative treatment effects of antiemetic medications not compared in head-to-head clinical trials. I will then explore the appropriateness of Bayesian methods to combine adult and child networks to improve the certainty of relative effect estimates in the paediatric population. I will also investigate whether, for an exemplar drug, this reliably predicts, the effect of new antiemetic medications, not yet licenced for use in children and young people.Aggregate data from clinical trials of eight modern antiemetic medications will be used in a first stage and then individual-level data from recent clinical trials in a second stage, also exploring treatment efficacy for multiple outcomes and interaction with patient characteristics such as age or type of chemotherapy received.Patient public involvement Patients (children of primary school age or older, or adults who were treated for cancer when they were a child or young person) and carers who have experience of CINV will be involved in prioritising outcomes of the project and interpreting and disseminate findings. This will be done through face-to-face activities and online meetings. To facilitate involvement, training on research methods will be provided for adolescents and adults. Feedback will be sought about the experience of those involved.Anticipated impactThis research aims to provide information to support better-informed decisions about which antiemetic agents to prescribe and for whom, without the need for additional clinical trials. Using adult clinical trial information may mean, full clinical trial programmes in children are not needed in the future to establish the effectiveness of new antiemetic medications, rather only confirmatory research will be needed, requiring fewer patients, resources, and costs. Findings will also inform the development of a framework for incorporating adult evidence into paediatric research.DisseminationFor patients and their families, I will create two short animation films and an easy-to-read summary of the findings that will be shared with children's cancer units. I will also engage with cancer charities to share these further. Findings will be submitted to peer-reviewed journals and to relevant conferences, and outputs fed back to the NIHR Academy.

Lay abstract: BackgroundChemotherapy is a treatment for cancer that can cause nausea (feeling sick) and vomiting (being sick). These unpleasant side effects are a problem for children and young people who are being treated for cancer, even though there are effective anti-sickness medicines available.Clinical trials investigate how well these anti-sickness medicines work. However, there are many more trials in adults than children, so we know less about how well different anti-sickness medicines prevent nausea and vomiting in children and young people. Children and young people are, therefore, not always given the best anti-sickness medicines and must sometimes wait years before new anti-sickness medicines given to adults become available for them. This means that often, children and young people will continue to feel and be sick during their chemotherapy treatment.Aims This research aims to find out which medicines work best at stopping nausea and vomiting in children and young people being treated for cancer, by gathering and analysing all the clinical trials that investigate this. When there is not enough evidence from childrens' clinical trials to answer this question, I will see if research done with adults, could improve our understanding of how well anti-sickness medicines stop nausea and vomiting in children and young people.MethodsI will use data from clinical trials done in children and young people to compare each anti-sickness medicine with every other, to find out which work best. Where there are no or few clinical trials comparing certain anti-sickness medicines in children and young people, I will find clinical trials comparing them in adults. I will use statistical methods to see if the data from these adult trials, can be used to reliably predict how well they work in children and young people.I will also ask for the 'raw' patient data from clinical trials. I will use this to improve our understanding of preventing nausea with anti-sickness medicines and explore whether some patients might benefit more from anti-sickness medicines than others. Patient public involvement I will work with patients (primary school age or older, or adults who were treated for cancer when they were a child or young person) and carers who have experienced nausea and vomiting during cancer treatment. Together we will prioritise which outcomes the project will look at, decide how to share the findings with patients and their families and present the findings at a conference. This will involve face-to-face activities and online meetings. To help young people and adults be involved, I will provide training for them on the research methods used in the PhD project. I will work with everyone involved to understand how we could learn from their experience of being part of the team, to improve such projects in the future.Anticipated impactFindings will provide information to help healthcare providers decide which medicines to prescribe, without the need for more clinical trials in children. They will also help patients and carers to understand their treatment options. Evidence from adult trials may in future, help to reach conclusions about new anti-sickness medicines for children and young people sooner, without needing to do so many trials in children and young people. Instead, smaller clinical trials could be used to confirm findings.Sharing the findingsTo reach those affected by childhood cancers, I will work with patients and their carers to create two short animation films and an easy-to-read summary, which will be shared in hospitals wards and cancer charities to reach a wider patient group. To reach healthcare providers and researchers, I will publish the findings as peer-reviewed journal articles and present at conferences.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS