Title: Developing a personalised approach to the treatment of fever with neutropenia (FN) for children and young people with cancer
Funder: Department of Health and Social Care

Abstract: Introduction: The commonest side effect of cancer therapies in childhood leading to an unplanned hospital admission is the suspicion of severe infection in an immunocompromised child, known as fever with neutropenia (FN). The management of FN currently consists of in-patient delivery of intravenous antibiotics. This approach produces low mortality rates but over-treats the 75% of individuals who do not have a documented infection. Accurate risk prediction could avoid hospitalisation and shorten treatment duration. A model predicting risk of significant complications of episodes of FN with clinical features has been derived as part of an international collaborative (PICNICC). This model requires external validation. Such risk predictions derived from clinical data may be further improved by incorporating biomarkers of inflammation or infection, and biomarkers may also help guide duration of therapy for in-patient treatment. Purely generating accurate predictions of the risk of a poor outcome is inadequate to inform and change practice, we also need to explore how this information may be used to allow effective ways of communicating predicted risk to support shared decision making. Objectives: To develop a personalised approach to the treatment of children and young people with fever with neutropenia (FN) with three linked projects:validation of a model predicting risk of significant complications of episodes of FNan evaluation of the predictive values of inflammatory biomarkersexploration of patient, parental and clinicians attitudes to making decisions in FNMethods and analysis:Prediction model validation (project 1) An individual participant data (IPD) synthesis will be performed. Collaborating groups will share datasets to validate a recently developed clinical prediction model of serious medical consequences for episodes of FN. The analysis will assess the discriminatory ability (by area under the receiver operating characteristic (AUC-ROC) curve, and the scaled Briers score) and calibration (estimating the calibration slope). If required, recalibration will adjust the intercept and/or calibration slope. Additional value of biomarkers (project 2) A primary cohort study in children and young people developing FN measuring the biomarkers procalcitonin, interleukin 6 and interleukin 8 will be undertaken as part of a planned prospective meta-analysis (where the results of similar studies are pooled). The study will collect serial measurements of these biomarkers. Their value in predicting serious medical complications will be assessed by hierarchical per-episode, per-person logistic regression. Their additional predictive value over clinical data (both the PICNICC model and a combination of temperature and clinical wellness) will be assessed for calibration and discrimination, as described in project 1. Comparisons between biomarkers will be made by AUC-ROC. Using better prediction information in decision making (project 3) Interviews with parents of children and young people who have experienced FN, and work with younger children using participatory methods will be conducted to explore the issues involved in making decisions about treating FN for clinicians, patients and their families. These data will be analysed by the Framework Method. The International Patient Decision Aid Standards Collaboration process will be followed to develop a decision aid. Outcomes and results: These studies will allow us to develop a framework to personalise our treatment of FN that can be evaluated in pragmatic trials. Ultimately, we may be able to shorten or avoid hospitalisation for some patients, reduce exposure to antibiotics for others, and respect the wishes of the patients and families to be involved in their care.

Lay abstract: Children and young people with cancer often develop fever with neutropenia (FN), which may indicate life-threatening infection. Current management is hospitalisation with intravenous antibiotics. I will evaluate a personalised approach to the management of children and young people with FN, assessing how well a clinical score predicts severe complications, and looking at the additional value of blood tests to clinical information. Interviews with clinicians, patients and families will explore how we can use these predictions to make decisions. Ultimately, this may be able to shorten or avoid hospitalisation and reduce antibiotic use, while respecting the wishes of patients and families.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS