Authors' objectives: Neutropenic sepsis is a common complication of systemic anticancer treatment. There is variation in practice in timing of switch to oral antibiotics after commencement of empirical intravenous antibiotic therapy. To establish the clinical and cost effectiveness of early switch to oral antibiotics in patients with neutropenic sepsis at low risk of infective complications. Neutropenic sepsis (NS) is a potentially life-threatening complication of treatment with systemic anticancer therapy (SACT). Many consensus guidelines, including the UK National Institute for Health and Care Excellence (NICE) guidance, recommend switching from intravenous (i.v.) to oral antibiotics after 48 hours of therapy, with evidence lacking to support an earlier switch in those patients at low risk of infective complications. The early switch to oral antibiotic therapy in patients with low-risk NS (EASI-SWITCH) trial was developed in response to a commissioned call by National Institute for Health and Care Research (NIHR) to address this evidence gap. To establish the clinical and cost effectiveness of early switch to oral antibiotics (within 12–24 hours of starting antibiotics) in patients with NS at low risk of infective complications. The primary objective was to assess whether early switch was non-inferior to standard care (continuation of i.v. antibiotics for at least 48 hours) in terms of treatment failure at day 14. The secondary objectives were to assess the effects of early oral switch on quality of life, length of hospital admission, re-admission to hospital, changes to subsequent planned SACT and death within 28 days in addition to an assessment of cost-effectiveness and patient preference for these treatment strategies at day 14.

Authors' results and conclusions: The study was closed early due to under-recruitment with 129 patients recruited; hence, a definitive conclusion regarding non-inferiority cannot be made. Sixty-five patients were randomised to the early switch arm and 64 to the standard care arm with subsequent intention-to-treat and per-protocol analyses including 125 (intervention n = 61 and control n = 64) and 113 (intervention n = 53 and control n = 60) patients, respectively. In the intention-to-treat population the treatment failure rates were 14.1% in the control group and 24.6% in the intervention group, difference = 10.5% (95% confidence interval 0.11 to 0.22). In the per-protocol population the treatment failure rates were 13.3% and 17.7% in control and intervention groups, respectively; difference = 3.7% (95% confidence interval 0.04 to 0.148). Treatment failure predominantly consisted of persistence or recurrence of fever and/or physician-directed escalation from protocolised antibiotics with no critical care admissions or deaths. The median length of stay was shorter in the intervention group and adverse events reported were similar in both groups. Patients, particularly those with care-giving responsibilities, expressed a preference for early switch. However, differences in health-related quality of life and health resource use were small and not statistically significant. Non-inferiority for early oral switch could not be proven due to trial under-recruitment. The findings suggest this may be an acceptable treatment strategy for some patients who can adhere to such a treatment regimen and would prefer a potentially reduced duration of hospitalisation while accepting increased risk of treatment failure resulting in re-admission. Further research should explore tools for patient stratification for low-risk de-escalation or ambulatory pathways including use of biomarkers and/or point-of-care rapid microbiological testing as an adjunct to clinical decision-making tools. This could include application to shorter-duration antimicrobial therapy in line with other antimicrobial stewardship studies. The embedded pilot phase of the study highlighted challenges in recruitment and study delivery but no concerns regarding treatment adherence or separation between treatment arms. Despite revisions to the study design and eligibility criteria, and taking account of the lower than anticipated incidence of NS, recruitment remained challenging and appeared to plateau as the study progressed. While logistical aspects such as the number of potential patients and the short time window for enrolment continued to impact on recruitment, review of standard care practice in NS management suggested increasing variation in equipoise between trial arms as clinicians shifted towards early or upfront oral antibiotics as the trial progressed. The study was closed early due to under-recruitment with 129 patients recruited. Sixty-five patients were randomised to the early switch (intervention arm) and 64 to the standard care (control) arm with subsequent ITT and PP analyses including 125 patients (intervention n = 61 and control n = 64) and 113 (intervention n = 53 and control n = 60), respectively. In the ITT population, the treatment failure rates were 14.1% in the control and 24.6% in the intervention group, respectively; difference = 10.5% (95% CI 0.11 to 0.22). In the PP population, the treatment failure rates were 13.3% and 17.7% in control and intervention groups, respectively; difference = 3.7% (95% CI 0.04 to 0.148). The criteria for non-inferiority were not met in the ITT analysis but were met in the PP analysis; however, given the under-recruitment, no definitive conclusion regarding non-inferiority can be made and the discordant results between ITT and PP analyses add to the uncertainty in interpreting these data. The main constituents of the composite primary outcome measure accounting for treatment failure were persistence/recurrence of fever and/or physician-directed escalation from the protocolised antibiotic regimen. None of the treatment failure events recorded in either arm were attributable to the need for critical care support or death before day 14. There were no apparent differences between the two trial arms for time to fever resolution, re-admission to hospital to day 28, survival to day 28 or changes to the originally intended SACT regimen. AEs were as anticipated for the agents used and reported at similar rates between treatment arms. A within-trial economic evaluation was performed to assess the cost effectiveness of early switch to oral antibiotics. This included a cost-effectiveness analysis (CEA) consistent with the primary outcome measure to estimate the cost per treatment failure avoided at day 14 and a CUA to estimate the cost per QALY at day 14. The primary measure used in these analyses, the QALY, was estimated from the EQ-5D-5L questionnaire. A bespoke Patient Follow-up Questionnaire at day 14 was used to collect information on non-health outcome measures important to patients. Overall, early oral switch appears to be a cost-effective approach within existing NHS care pathways and leads to improvements in global HRQoL. The majority of patients were content with the treatment they received, regardless of the group they were randomised to. Notably, patients had a much higher acceptance of the possibility of treatment failure in order to enable early discharge for their primary admission than might be anticipated by clinicians. Non-inferiority for early oral switch could not be proven. The findings suggest this may be a an acceptable treatment strategy for some patients who can adhere to such a treatment regimen and would prefer a potentially reduced duration of hospitalisation while accepting a potentially increased risk of treatment failure resulting in re-admission.

Authors' methods: A randomised, multicentre, open-label, allocation concealed, non-inferiority trial to establish the clinical and cost effectiveness of early oral switch in comparison to standard care. Nineteen UK oncology centres. Patients aged 16 years and over receiving systemic anticancer therapy with fever (≥ 38°C), or symptoms and signs of sepsis, and neutropenia (≤ 1.0 × 109/l) within 24 hours of randomisation, with a Multinational Association for Supportive Care in Cancer score of ≥ 21 and receiving intravenous piperacillin/tazobactam or meropenem for

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/13/140/05

Year Published: 2024

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/RGTP7112

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/RGTP7112

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk