Robenshtok, E., Gafter-Gvili, A., Goldberg, E., Weinberger, M., Yeshurun, M., Leibovici, L., & Paul., M. (2007). Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. Journal of Clinical Oncology, 25, 5471–5489.

To determine the effect of antifungal prophylaxis on all-cause mortality, invasive fungal infections (IFIs), and adverse events in patients with cancer treated with chemotherapy or hematopoietic stem cell transplantation (HSCT).

Databases searched were PubMed (January 1966–January 2007) and the Cochrane Library (CENTRAL) (through 2007).  Conference proceedings in oncology, hematology, and infectious diseases were also searched. The references of all included trials and reviews were searched for additional studies.

Search keywords were neutropenia, chemotherapy and similar, specific antifungals or antifungal and similar, and prophylaxis and similar.

The authors included studies that were randomized, controlled trials comparing a systemic antifungal drug with placebo, no intervention, or other antifungal agents for prophylaxis of fungal infections in afebrile patients with cancer after chemotherapy or hematopoietic cell transplantation (HCT).

Studies were excluded if they lacked a randomized, controlled design or used empiric or pre-emptive antifungal therapy.

• One hundred twenty-four studies were initially reviewed.
• Sixty-four studies were included in the report.
• Study quality was evaluated using the Oxford scale.

• The total sample size comprised 64 randomized, controlled trials. 
• The sample size across all included studies ranged from 24 to 889.
• Thirty-five trials included a majority (>70%) of patients with hematologic malignancies (mostly acute leukemia but also lymphoma, chronic myelocytic leukemia in blast crisis, high-risk myelodysplastic syndromes, and multiple myeloma).
• Fifteen studies included patients who underwent bone marrow transplantation.
• Fourteen trials included a mixed population of patients with solid tumors or hematologic malignancies and those who had undergone HSCT.
• Children were included in five trials.

Systemic Antifungals Versus Placebo, No Treatment, or Nonsystemic Antifungals All-Cause Mortality

• In 31 trials that reported all-cause mortality, antifungal prophylaxis decreased the risk of mortality significantly at the end of follow-up (relative risk [RR] = 0.84; 95% confidence interval [CI] [0.74, 0.95]), with no significant heterogeneity (p = 0.46; I² = 0.7%).
• The number of patients needed to treat to prevent one death at end of follow-up was 43 (95% CI, [26, 138], with a control group mortality rate of 15%). 

Subgroup Analysis

• Antifungal prophylaxis resulted in a significant reduction in mortality in allogeneic HSCT (four trials; RR = 0.62; 95% CI [0.45, 0.85]) and autologous HSCT (one trial; RR = 0.27; 95% CI [0.08, 0.9526]).
• One trial, which included 52% autologous and 48% allogeneic HSCT recipients, showed no survival advantage with prophylaxis.
• There was a borderline statistically significant reduction in mortality at the end of follow-up among patients with acute leukemia, mostly undergoing induction therapy (24 trials; RR = 0.88; 95% CI [0.74, 1.06]).
• There was a nonsignificant reduction in mortality in other malignancies (12 trials; RR = 0.83; 95% CI [0.62, 1.11]).  

Specific Antifungals

• Fluconazole prophylaxis reduced early (day 30 posttreatment) mortality significantly (13 trials; RR = 0.78; 95% CI [0.64, 0.95]) and with borderline significance (15 trials; RR = 0.88; 95% CI [0.75, 1.02]) at the end of follow-up.
• Intravenous (IV) amphotericin B significantly reduced mortality at the end of follow-up (two trials; RR = 0.31; 95% CI [0.13, 0.72]).
• Trials in which itraconazole was administered as oral suspension demonstrated a significant reduction of documented IFIs (RR = 0.58; 95% CI [0.34, 0.98]) and of documented candida infections (RR = 0.35; 95% CI [0.14, 0.84]) in the itraconazole group. In this subset of trials, there was a trend toward more invasive aspergillus infections in the fluconazole arm (RR = 1.35; 95% CI [0.82, 2.21]).
• The RRs for the indirect comparison of fluconazole versus itraconazole for mortality was 1.0 (22 trials; 95% CI [0.67, 1.33]); the same comparison for IFIs was 0.68 (27 trials; 95% CI [0.18, 1.19]).

Fluconazole Versus IV Amphotericin B

• Three trials (two included patients undergoing HSCT and one included patients with acute leukemia) compared oral fluconazole versus low-dose IV amphotericin B (0.2 mg/kg once daily or 0.5 mg/kg three times a week), and no difference was noted in all-cause mortality, fungal-related mortality, any (documented, probable, and possible) IFIs, documented candida or aspergillus infections, and superficial fungal infections.
• Fluconazole resulted in a significant reduction of documented IFIs (RR = 0.49; 95% CI [0.28, 0.86]).
• There were more adverse events in the amphotericin group, necessitating discontinuation of the drug (RR = 6.67; 95% CI [2.6, 16.7]).

Posaconazole Versus Fluconazole or Itraconazole

• Two studies compared oral posaconazole with oral fluconazole or itraconazole (itraconazole in a small subgroup in one trial; 58 of 298 patients in the non-posaconazole arm) in patients with acute leukemia undergoing induction chemotherapy and patients after HSCT with graft-versus-host disease.
• The use of posaconazole compared with fluconazole or itraconazole resulted in a reduction in all-cause mortality of borderline statistical significance (RR = 0.77; 95% CI [0.59, 1.01]).
• When posaconazole was compared with fluconazole alone (data provided from the author), there was a significant reduction in all-cause mortality (RR = 0.74; 95% CI [0.56, 0.98]).
• Posaconazole prophylaxis also resulted in a significant reduction in fungal-related mortality (RR = 0.25; 95% CI [0.11, 0.57]) and in documented or probable IFIs (RR = 0.47; 95% CI [0.3, 0.74]).
• Posaconazole prophylaxis yielded a significant reduction in documented invasive aspergillus infections (RR = 0.22; 95% CI [0.11, 0.42]).
• There was no difference in the prevalence of adverse reactions causing discontinuation of the study drug (RR = 0.88; 95% CI [0.66, 1.17]).

Fluconazole Versus Antifungals with Antimold Activity

• There was a trend toward higher all-cause mortality with fluconazole (12 trials; RR = 1.14; 95% CI [0.95, 1.37]), which originated mostly from the comparison with posaconazole (two trials) and micafungin (one trial).
• Compared with antifungals that have antimold activity, fluconazole was associated with a significantly higher rate of fungal-related mortality, any IFI, and IFIs caused by the aspergillus species.

Other Trials

• Seven trials compared two regimens of systemic antifungals—comparisons that were not repeated in other trials.
• In patients undergoing HSCT, micafungin prophylaxis was superior to fluconazole in overall success rate, with no difference in mortality, and the combination of micafungin and fluconazole versus fluconazole alone showed similar efficacy. 
• A comparison of a low dose (200 mg) versus a high dose (400 mg) of fluconazole resulted in comparable efficacy. 
• In patients with high-risk acute leukemia, voriconazole prophylaxis decreased IFIs at the cost of more adverse reactions when compared with itraconazole.
• One study that compared amphotericin B colloidal dispersion with fluconazole was terminated prematurely because of a high rate of adverse events with amphotericin B colloidal dispersion.
• IV caspofungin and itraconazole provided similar protection against IFIs, and liposomal amphotericin B prophylaxis resulted in similar efficacy as the combination of itraconazole and fluconazole.

Current data support the use of fluconazole, itraconazole suspension, or posaconazole for prophylaxis.

Antifungal prophylaxis in patients with solid tumors and autologous HCT is not recommended. Prophylaxis should be administered to patients with acute leukemia during induction chemotherapy and to other patients with high-risk leukemia.