Pre-emptive antifungal therapy versus empirical antifungal therapy for febrile neutropenia in people with cancer

Background Intensive cytotoxic chemotherapy for people with cancer can cause severe and prolonged cytopenia, especially neutropenia, a critical condition that is potentially life-threatening. When manifested by fever and neutropenia, it is called febrile neutropenia (FN). Invasive fungal disease (IFD) is one of the serious aetiologies of chemotherapy-induced FN. In pre-emptive therapy, physicians only initiate antifungal therapy when an invasive fungal infection is detected by a diagnostic test. Compared to empirical antifungal therapy, preemptive therapy may reduce the use of antifungal agents and associated adverse eFects, but may increase mortality. The benefits and harms associated with the two treatment strategies have yet to be determined. Objectives To assess the relative eFicacy, safety, and impact on antifungal agent use of pre-emptive versus empirical antifungal therapy in people with cancer who have febrile neutropenia. Search methods We searched CENTRAL, MEDLINE Ovid, Embase Ovid, and ClinicalTrials.gov to October 2021. Selection criteria We included randomised controlled trials (RCTs) that compared pre-emptive antifungal therapy with empirical antifungal therapy for people with cancer. Data collection and analysis We identified 2257 records from the databases and handsearching. AHer removing duplicates, screening titles and abstracts, and reviewing full-text reports, we included seven studies in the review. We evaluated the eFects on all-cause mortality, mortality ascribed to fungal infection, proportion of antifungal agent use (other than prophylactic use), duration of antifungal use (days), invasive fungal infection detection, and adverse eFects for the comparison of pre-emptive versus empirical antifungal therapy. We presented the overall certainty of the evidence for each outcome according to the GRADE approach.Main results This review includes 1480 participants from seven randomised controlled trials. Included studies only enroled participants at high risk of FN (e.g. people with haematological malignancy); none of them included participants at low risk (e.g. people with solid tumours). Low-certainty evidence suggests there may be little to no diFerence between pre-emptive and empirical antifungal treatment for all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.72 to 1.30; absolute eFect, reduced by 3/1000); and for mortality ascribed to fungal infection (RR 0.92, 95% CI 0.45 to 1.89; absolute eFect, reduced by 2/1000). Pre-emptive therapy may decrease the proportion of antifungal agent used more than empirical therapy (other than prophylactic use; RR 0.71, 95% CI 0.47 to 1.05; absolute eFect, reduced by 125/1000; very low-certainty evidence). Pre-emptive therapy may reduce the duration of antifungal use more than empirical treatment (mean diFerence (MD) -3.52 days, 95% CI -6.99 to -0.06, very low-certainty evidence). Pre-emptive therapy may increase invasive fungal infection detection compared to empirical treatment (RR 1.70, 95% CI 0.71 to 4.05; absolute eFect, increased by 43/1000; very low-certainty evidence). Although we were unable to pool adverse events in a meta-analysis, there seemed to be no apparent diFerence in the frequency or severity of adverse events between groups. Due to the nature of the intervention, none of the seven RCTs could blind participants and personnel related to performance bias. We identified considerable clinical and statistical heterogeneity, which reduced the certainty of the evidence for each outcome. However, the two mortality outcomes had less statistical heterogeneity than other outcomes.