Ziakas, P.D., Kourbeti, I.S., Voulgarelis, M., & Mylonakis, E. (2010). Effectiveness of systemic antifungal prophylaxis in patients with neutropenia after chemotherapy: a meta-analysis of randomized controlled trials. Clinical Therapeutics, 32, 2316–2336.

To estimate the impact of antifungal prophylaxis on the occurrence of proven systemic fungal infections in patients with neutropenia and to quantify its effect on mortality attributed to these infections.

Databases searched were MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through September 15, 2010.  In addition, proceedings of the annual meetings of the Infectious Diseases Society of America (2001–2009), the American Society of Hematology (2000–2009), and the European Society of Clinical Microbiology and Infectious Diseases (2000–2010) were manually reviewed.

Search keywords were clinical trial(s), neutropenia, neoplasms, malignant, malignant neoplasm, mycoses, candida, aspergillus, zygomycosis, antifungal agents/antifungal, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, amphotericin B, miconazole, and micafungin.

Articles were included if they focused on patients undergoing treatment for cancer who received prophylactic antifungal medications.

Articles were excluded if they directly compared systemic antifungal prophylactic agents, evaluated nonabsorbable polyenes or oral antifungal formulations of amphotericin B, and did not evaluate antifungals prophylactically (i.e., those that included empirical, pre-emptive, or salvage therapies for fungal mycoses).
 

A total of 11,418 references were retrieved.

A meta-analysis method of study was used. In specific, statistical analysis was performed to compare study results, including effects of antifungal prophylaxis using random effects and reported as pooled odds ratios (ORs) and 95% confidence intervals (CIs) using the Robins-Breslow-Greenland formula.  For study cells with zero events, an ad hoc treatment arm continuity correction was used.  Findings in which the 95% CI crossed 1 were not considered statistically significant. Statistical heterogeneity was assessed using the I² statistic and Cochrane Q test. The Petro method was used for sensitivity analysis, and the Harbord modification of the Egger test was used to evaluate small study effects for major outcomes.

• After exclusion factors, 26 articles remained in total and 25 were included in the analysis of the outcomes.  
• The total sample across all articles was 3,979.
• Sample sizes per article ranged from 25 to 405.
• Median age ranged from 7 to 65 years across studies. The majority of patients had hematologic malignancies treated with or without hematopoietic stem cell transplantation (HSCT), and five studies included patients with solid tumors. Specific diagnoses were not disclosed.

Patients were undergoing the active treatment phase of care.

Antifungal prophylaxis was associated with statistically significant reductions in proven fungal infections (OR = 0.43; 95% CI [0.31, 0.6]; number needed to treat [NNT] = 20) and mortality attributed to fungal infections (OR = 0.49; 95% CI [0.3, 0.8]; NNT = 53), reduction in risk for proven candida infections (OR = 0.28; 95% CI [0.2, 0.38]), and a decreased need for antifungal therapy (OR = 0.64; 95% CI [0.48, 0.86]). Explanatory subanalysis of major outcomes showed a reduced risk for proven infections among HSCT recipients only (OR = 0.27; 95% CI [0.16, 0.44]) and infection-related mortality (OR = 0.41; 95% CI [0.21, 0.81]). Not statistically significant were overall mortality (OR = 0.92; 95% CI [0.74, 1.14]) or reduction of aspergillosis or zygomycosis. Meta-regression analysis showed that multi-center and double-blind designs were significant moderators of the effect of antifungal prophylaxis on overall mortality and proven systemic fungal infections.

Systemic antifungal prophylaxis was associated with decreased proven fungal infections and fungal infection-related mortality in patients with neutropenia following chemotherapy.  Antifungal prophylaxis was also associated with decreased proven infections and infection-related mortality in HSCT recipients.  Overall mortality was not improved through the use of antifungal prophylactic therapy.

 The use of prophylactic antifungal therapy should be considered for patients receiving neutropenic-inducing chemotherapy and/or those undergoing HSCT.