Review: Voriconazole for prevention or treatment of invasive fungal infections in cancer with neutropenia

Question In patients with cancer and neutropenia, what are the efficacy and safety of voriconazole compared with amphotericin B or fluconazole for preventing or treating invasive fungal infections? Review scope Included studies compared voriconazole with amphotericin B or fluconazole, given intravenously or orally, in patients with cancer complicated by neutropenia. Studies that assessed treatment or prevention of oral candidiasis only were excluded. Outcomes included mortality, invasive fungal infection, and use of escape antifungal therapy. Review methods MEDLINE and Cochrane CENTRAL (both to Jan 2014) were searched for published or unpublished randomized controlled trials (RCTs). Reference lists were searched, and authors and drug manufacturers were consulted. 3 RCTs (n =1862) met the selection criteria. 1 unblinded RCT compared voriconazole with liposomal amphotericin B for empirical treatment of febrile neutropenia (n =871), 1 unblinded RCT compared voriconazole with amphotericin B deoxycholate for invasive Aspergillus infection (n =391), and 1 double-blind RCT compared voriconazole with fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplantation (n =600). Main results Data were not pooled because of heterogeneity in trial design. Results are shown in the Table. Conclusions Voriconazole does not differ from fluconazole for prevention of fungal infections, but it reduces death compared with amphotericin when used for invasive Aspergillus infection. Voriconazole is not noninferior to liposomal amphotericin for treatment of febrile neutropenia in cancer. Voriconazole vs control for preventing or treating invasive fungal infections in cancer complicated by neutropenia Outcomes Control Findings Mortality Liposomal amphotericin B No difference at 30 d Amphotericin B Reduced mortality at 84 d Fluconazole No difference at 100 d Invasive fungal infection Liposomal amphotericin B No difference Amphotericin B No difference at 84 d Fluconazole No difference in fungal-free survival at 180 d Use of escape antifungal therapy Fluconazole No difference Commentary The systematic review of by Jrgensen and colleagues includes 3 studies of voriconazole's efficacy and safety as they relate to prevention and treatment of invasive fungal infections. Voriconazole is an azole with greater activity against filamentous fungi than fluconazole (1). It has an advantage over amphotericin B (deoxycholate and liposomal) because of its perceived superior side effect profile and the availability of an oral formulation. Voriconazole is also widely assumed to be better for invasive aspergillosis than amphotericin B deoxycholate (2). The broad objective of this review predictably led to heterogeneity of the included trials. Eligibility criteria, outcomes, search methods, and the approach to data synthesis were rigorous. Criticism by the reviewers of the noninferiority treatment trial comparing voriconazole with liposomal amphotericin (3) (lack of blinding, blocks of 2, failure to account for all patients randomized) can be readily appreciated. The reviewers' conclusion that liposomal amphotericin is significantly better than voriconazole, however, was based on trial data sent by the sponsor of the trial to the US Food and Drug Administration (4). In the trial comparing voriconazole to amphotericin B for treatment of invasive aspergillosis (2), better responses with improved survival were appropriately reported, yet these data were dismissed by the reviewers who would have preferred liposomal amphotericin as the comparator. Although a critique of choice of comparator is legitimate, discarding the results entirely is questionable.