title: Voriconazole versus amphotericin B or fluconazole in cancer patients with neutropenia.
abstract: BACKGROUND
  Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy is used both empirically and therapeutically in these patients.
  
  
  OBJECTIVE
  To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia.
  
  
  METHODS
  Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 1 2014), MEDLINE (to January 2014). Letters, abstracts and unpublished trials were accepted. Contact was made with trial authors and industry.
  
  
  METHODS
  Randomised clinical trials comparing voriconazole with amphotericin B or fluconazole.
  
  
  METHODS
  Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted independently by two review authors.
  
  
  RESULTS
  Three trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infection) in neutropenic cancer patients (849 patients, 58 deaths). The second trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). The third trial compared fluconazole to voriconazole for prophylaxis of fungal infections in patients receiving allogeneic stem cell transplantation (600 patients, number of deaths not stated). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the trial authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from the analysis by the trial authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication to counter side effects and replacement of electrolytes or use of salt water. This choice of comparator resulted in a marked difference in the duration of treatment on the trial drugs (77 days with voriconazole versus 10 days with amphotericin B) and precluded meaningful comparisons of the benefits and harms of the two drugs. The third trial failed to find a difference in fungal free survival or invasive fungal infections at 180 days when voriconazole was compared to fluconazole.
  
  
  CONCLUSIONS
  Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of fungal infections in neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions. For prophylactic fungal treatment in patients receiving allogeneic stem cell transplantation, there was no difference between voriconazole and fluconazole regarding fungal free survival or invasive fungal infections.
authors.affiliation: The Nordic Cochrane Centre, Rigshospitalet, Blegdamsvej 9, 7811, Copenhagen, Denmark, 2100.
authors.forename: Karsten Juhl
authors.initials: KJ
authors.lastname: Jørgensen
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gøtzsche
authors.forename: Christina S
authors.initials: CS
authors.lastname: Dalbøge
authors.forename: Helle Krogh
authors.initials: HK
authors.lastname: Johansen
mesh_terms: D000666:Amphotericin B / Q000009:adverse effects / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy; D015725:Fluconazole / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008081:Liposomes; D009181:Mycoses / Q000188:drug therapy* / Q000401:mortality; D009369:Neoplasms / Q000150:complications*; D009503:Neutropenia / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D009894:Opportunistic Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D014230:Triazoles / Q000009:adverse effects / Q000627:therapeutic use*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D008081:Liposomes; D011743:Pyrimidines; D014230:Triazoles; D000666:Amphotericin B; D015725:Fluconazole; D065819:Voriconazole