Ethier, M.C., Science, M., Beyene, J., Briel, M., Lehrnbecher, T., & Sung, L. (2012). Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials. British Journal of Cancer, 106, 1626–1637.

To research the evidence regarding the use of mold-active versus fluconazole prophylaxis in hematopoietic stem cell transplantation (HSCT) recipients.

Databases searched were Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials.  The authors also searched ClinicalTrials.gov, study reference lists via handsearching, Web of Science, and abstracts from the American Society of Clinical Oncology annual meetings for the past two years.

Search keywords were fluconazole, aspergillus or mycoses, prevention or prophylaxis, neoplasm, stem cell transplantation, and neutropenia.

Sources were included if they

• Were randomized, controlled trials comparing mold-active to fluconazole prophylaxis.
• Included randomization between fluconazole and any mold-active agent.
• Included patients of any age undergoing chemotherapy or HSCT.

Sources were excluded if more than one systemic prophylactic antifungal agent was given in a single study arm; pre-emptive or empiric therapy or antifungal treatment was reported; and if they did not report primary or secondary outcomes of invasive fungal infection (IFI) proven or probable, IFI-related mortality, all cause mortality, and adverse events.

Nine hundred eighty-four references were retrieved. Risk of bias was evaluated using definitions derived from the Cochrane Handbook for Systematic Reviews of Interventions.

• The final number of studies included was 20, with 5,725 total patients. Sample sizes per study ranged from 24 to 882.
• All participants had hematologic malignancies or had received allogeneic or autologous HSCT.
• Age ranged from 6 months to 82 years.
• Fifty percent were multi-center studies.
• Children were included in four trials.

• The phase of care was active antitumor treatment.
• The application was for pediatrics.

Study regimens included amphotericin B formulations, micafungin, posaconazole, voriconazole, and itraconazole. 

The majority of studies did not provide adequate information on randomization and allocation concealment. Six of 20 studies completed intention-to-treat analysis. 

Mold-active prophylaxis compared to fluconazole significantly reduced the risk of IFI (relative risk [RR] = 0.71; 95% confidence interval [CI], [0.52, 0.98]; p = 0.03). Mold-active prophylaxis decreased the risk of aspergillus infection (RR = 0.53; 95% CI [0.37, 0.75]) and IFI-related mortality (RR = 0.67; 95% CI [0.47, 0.96]); however, it did not influence overall mortality. Use of mold-active agents was associated with more adverse events leading to discontinuation of antifungal prophylaxis (RR = 1.95; 95% CI [1.24, 3.07]; p = 0.004). Types of adverse events are not described.

Prophylaxis with mold-active agents compared with fluconazole prophylaxis significantly reduced the number of proven and probable IFI and aspergillus infections in these types of patients. However, these agents were also associated with increased adverse events that necessitated stopping antifungal prophylaxis. Findings also suggested that use of mold-active agents did not affect overall mortality, although use did affect IFI-related mortality. Fluconazole is generally less expensive than some mold-active agents, and amphotericin B is not available in an oral form. Further study of the relative benefits and harms with various approaches for antifungal prophylaxis in this group of patients is warranted, and additional study is needed to better understand the full role of antifungal prophylaxis in overall survival in these patients.

Many studies had design issues regarding the description of randomization and lack of blinding. The types of adverse events observed were not provided, and clinical severity leading to study discontinuation are not described. The prophylaxis endpoint of included studies varied—some were based on absolute neutrophil count (ANC), and some were simply time-limited. ANC endpoints varied across studies. It is unclear if all studies involved primary prophylaxis or included secondary prophylaxis.

Findings suggested that antifungal prophylaxis with agents, such as amphotericin B, micafungin, posaconazole, voriconazole, and itraconazole, appears to be more effective in the prevention of invasive fungal infection and aspergillus infection than routine prophylaxis with fluconazole; however, these agents were also associated with a much greater risk of adverse events. Selection of approach for antifungal prophylaxis necessitates weighing the risks and benefits of both approaches for individual patients. Findings suggest that this type of comparison for secondary prophylaxis is worth evaluating as well.