Timing and clinical burden of febrile neutropenia and treatment discontinuation during neoadjuvant chemotherapy

BACKGROUND: Febrile neutropenia (FN) remains a major complication of neoadjuvant chemotherapy (NAC) and is a frequent cause of treatment disruption. However, FN is a heterogeneous clinical entity, and the impact of its timing and clinical severity on treatment continuity has not been fully elucidated. This study aimed to characterize the timing and clinical burden of FN and to clarify their associations with treatment discontinuation during NAC. METHODS: We retrospectively analyzed 137 consecutive patients with HER2-positive breast cancer who received NAC. FN timing was assessed by chemotherapy cycle and days from NAC initiation, with early FN defined a priori as FN occurring at cycle ≤ 2. FN severity was evaluated based on the requirement for hospitalization. Treatment discontinuation was defined as premature discontinuation of NAC due to chemotherapy-related adverse events; dose reductions or treatment delays without permanent discontinuation were not included in this endpoint. Logistic regression analyses were performed to identify factors associated with treatment discontinuation. RESULTS: FN occurred in 18 patients (13.1%). The median time to FN onset was 46 days (interquartile range, 19-112), with half of FN events occurring by cycle 2. Although FN events were evenly distributed across chemotherapy cycles, cumulative incidence analysis revealed early clustering on a time-based scale. Hospitalization was required in 50.0% of patients with FN. Treatment discontinuation occurred in 8.4% of patients without FN, 11.1% of patients with non-hospitalized FN, and 44.4% of patients with hospitalized FN. Exploratory multivariable analyses demonstrated that hospitalized FN was associated with treatment discontinuation after adjustment for age and host-related factors (odds ratio, 11.20-13.33 across models), whereas low body mass index and reduced renal function were not independent predictors. CONCLUSIONS: The impact of FN on treatment continuity during NAC appears to be determined by both its timing and clinical severity. FN requiring hospitalization, particularly when occurring early during NAC, was associated with an increased likelihood of treatment discontinuation. These findings underscore the importance of early identification and prevention of severe FN to optimize treatment delivery during neoadjuvant chemotherapy, while recognizing the statistical uncertainty inherent to the limited number of events.