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. 2022 Nov 28;11(11):CD013604.
doi: 10.1002/14651858.CD013604.pub2.

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

Yu Uneno  1 , Haruki Imura  2 , Yosuke Makuuchi  3 , Kentaro Tochitani  4 , Norio Watanabe  5
Affiliations

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

Yu Uneno et al. Cochrane Database Syst Rev. .

Abstract

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, pre-emptive therapy may reduce the use of antifungal agents and associated adverse effects, but may increase mortality. The benefits and harms associated with the two treatment strategies have yet to be determined. OBJECTIVES: To assess the relative efficacy, 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. After removing duplicates, screening titles and abstracts, and reviewing full-text reports, we included seven studies in the review. We evaluated the effects 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 effects 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 difference 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 effect, reduced by 3/1000); and for mortality ascribed to fungal infection (RR 0.92, 95% CI 0.45 to 1.89; absolute effect, 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 effect, reduced by 125/1000; very low-certainty evidence). Pre-emptive therapy may reduce the duration of antifungal use more than empirical treatment (mean difference (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 effect, 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 difference 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.

Authors' conclusions: For people with cancer who are at high-risk of febrile neutropenia, pre-emptive antifungal therapy may reduce the duration and rate of use of antifungal agents compared to empirical therapy, without increasing over-all and IFD-related mortality; but the evidence regarding invasive fungal infection detection and adverse events was inconsistent and uncertain.

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Conflict of interest statement

Yu Uneno: none known Haruki Imura: none known Yosuke Makuuchi: has received lecture fees from Merck, Sharp and Dohme and Bristol‐Myers Squibb on topics outside the scope of this review. Kentaro Tochitani: none known Norio Watanabe: none known

Figures

1
1
PRISMA flow diagram, illustrating study selection
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
1.1
1.1. Analysis
Comparison 1: Pre‐emptive versus empirical antifungal therapy, Outcome 1: All‐cause mortality
1.2
1.2. Analysis
Comparison 1: Pre‐emptive versus empirical antifungal therapy, Outcome 2: Mortality ascribed to fungal infection
1.3
1.3. Analysis
Comparison 1: Pre‐emptive versus empirical antifungal therapy, Outcome 3: Proportion of antifungal agent use (other than prophylactic use)
1.4
1.4. Analysis
Comparison 1: Pre‐emptive versus empirical antifungal therapy, Outcome 4: Duration of antifungal use (days)
1.5
1.5. Analysis
Comparison 1: Pre‐emptive versus empirical antifungal therapy, Outcome 5: Invasive fungal infection detection
2.1
2.1. Analysis
Comparison 2: Sensitivity analyses for all‐cause mortality, Outcome 1: RCTs at lower risk of bias
2.2
2.2. Analysis
Comparison 2: Sensitivity analyses for all‐cause mortality, Outcome 2: Replacing outcomes for Hebart 2009
2.3
2.3. Analysis
Comparison 2: Sensitivity analyses for all‐cause mortality, Outcome 3: Short‐term time point
2.4
2.4. Analysis
Comparison 2: Sensitivity analyses for all‐cause mortality, Outcome 4: Medium‐term time point
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  • doi: 10.1002/14651858.CD013604

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