Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials

Abstract

Background: The overall clinical efficacy of the azoles antifungal agents and low-dose intravenous amphotericin B for antifungal chemoprophylaxis in patients with malignant disease who have severe neutropenia remains unclear.

Methods: Randomized-controlled trials of azoles (fluconazole, itraconazole, ketoconazole, and miconazole) or intravenous amphotericin B formulations compared with placebo/no treatment or polyene-based controls in severely neutropenic chemotherapy recipients were evaluated using meta-analytical techniques.

Results: Thirty-eight trials that included 7014 patients (study agents, 3515 patients; control patients, 3499 patients) were analyzed. Overall, there were reductions in the use of parenteral antifungal therapy (prophylaxis success: odds ratio [OR], 0.57; 95% confidence interval [95% CI], 0.48-0.68; relative risk reduction [RRR], 19%; number requiring treatment for this outcome [NNT], 10 patients), superficial fungal infection (OR, 0.29; 95% CI, 0.20-0.43; RRR, 61%; NNT, 12 patients), invasive fungal infection (OR, 0.44; 95% CI, 0.35-0.55; RRR, 56%; NNT, 22 patients), and fungal infection-related mortality (OR, 0.58; 95% CI, 0.41-0.82; RRR, 47%; NNT, 52 patients). Invasive aspergillosis was unaffected (OR, 1.03; 95% CI, 0.62-1.44). Although overall mortality was not reduced (OR, 0.87; 95% CI, 0.74-1.03), subgroup analyses showed reduced mortality in studies of patients who had prolonged neutropenia (OR, 0.72; 95% CI, 0.55-0.95) or who underwent hematopoietic stem cell transplantation (HSCT) (OR, 0.77; 95% CI, 0.59-0.99). The multivariate metaregression analyses identified HSCT, prolonged neutropenia, acute leukemia with prolonged neutropenia, and higher azole dose as predictors of treatment effect.

Conclusions: Antifungal prophylaxis reduced morbidity, as evidenced by reductions in the use of parenteral antifungal therapy, superficial fungal infection, and invasive fungal infection, as well as reducing fungal infection-related mortality. These effects were most pronounced in patients with malignant disease who had prolonged neutropenia and HSCT recipients.