39·0°C versus 38·5°C ear temperature as fever limit in children with neutropenia undergoing chemotherapy for cancer: A multicentre, cluster-randomised, multiple-crossover, non-inferiority trial

1. In children with neutropenia and chemotherapy for cancer, 39·0°C ear temperature as a threshold for fever is non-inferior to 38·5°C for safety and appeared efficacious.

Evidence Rating Level: 1 (Excellent)

Febrile neutropenia is the most frequent complication of chemotherapy. Currently, the temperature limit defined for children varies across different treatment centres, which may lead to unnecessary medical intervention for patients spontaneously recovering from fever when thresholds are set too low. In this cluster-randomised, multiple crossover, non-blinded, non-inferiority trial, Swiss researchers sought to determine whether a fever threshold of 39•0°C as a fever limit would be non-inferior to 38•5°C in terms of safety. Two hundred and sixty nine patients aged 1 to 18 with a malignancy treated by myelosuppressive chemotherapy were repeatedly randomly assigned to monthly limits of either 39•0°C or 38•5°C ear temperature limits for diagnosis in neutropenia. To assess non-inferiority, the primary outcome was rate of febrile neutropenia with safety relevant events (SRE) per chemotherapy year, with a non-inferiority margin of 1.33 for safety, and a superiority margin of 1.00 for superiority. Following 2547 total randomization periods and 195 chemotherapy years, SREs were diagnosed in 72 (20%) of 360 febrile neutropenia episodes, consisting of 16 ICU admissions, 22 cases of severe sepsis, and 56 cases of bacteremia. In 92 chemotherapy years randomised to the higher fever limit, 151 episodes of fever with neutropenia were diagnosed (1·64 per year), including 22 (15%) with SRE (0·24 per year), compared to 209 diagnosed episodes (2·03 per year), and 50 cases (24%) with SRE (0·49 per year) in the 38•5°C group. In mixed Poisson regression analysis, the rate ratio of febrile neutropenia was 0.83 when comparing the 39•0°C to the 38•5°C group, with the RR for febrile with SRE at 0.56 (upper limit of 95% CI, 0.72), well within limits of noninferiority. Findings suggest that setting a higher fever limit for children on chemotherapy treatment was both safe and efficacious, which may be recommended as the new standard to prevent unnecessary medical intervention. Further investigation will be needed to improve generalizability of findings however, in different nations and for patients with acute myeloid leukemia or hematopoietic stem cell transplantation.

Click to read the study in The Lancet

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