Voriconazole versus amphotericin B or fluconazole in cancer patients with neutropenia Stable (no update expected for reasons given in 'What's new')

Abstract

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.

Objectives

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.

Search 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 Letters, abstracts and unpublished trials were accepted.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.

Selection criteria

Randomised clinical trials comparing voriconazole with amphotericin B or fluconazole.

Data collection and analysis

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.

Main 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.

Authors' 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.

Author(s)

Karsten Juhl Jørgensen, Peter C Gøtzsche, Christina S Dalbøge, Helle Krogh Johansen

Abstract

Plain language summary

Is voriconazole better than amphotericin B or fluconazole to prevent and treat fungal infections in cancer patients with poor immune defence systems 

Background 

Patients with cancer who are treated with chemotherapy or receive a bone marrow transplant have an increased risk of fungal infections. Such infections can be life‐threatening. Antifungal drugs are therefore often given to prevent fungal infections in such patients, either when these patients are known to have a fungal infection or when such an infection is suspected. We reviewed the evidence about the effect of voriconazole compared to amphotericin B or fluconazole to prevent or treat fungal infections in cancer patients with a poor immune system to provide defence.

Study characteristics 

We identified three studies. Our most recent search for studies was done in January 2014.

One trial compared voriconazole to liposomal amphotericin B in 849 men and women (58 deaths) with cancer and a poor immune system. Treatment was most often given for seven days. The treatment was provided in patients where a fungal infection was suspected because they had a fever that could not otherwise be explained.

The second trial compared voriconazole to amphotericin B deoxycholate in 391 men and women (98 deaths) with cancer and a poor immune system. Voriconazole was given for 77 days on average whereas liposomal amphotericin B deoxycholate was given for 10 days on average. The treatment was given when patients were known or suspected to have a specific fungal infection (Aspergillus).

The third trial compared voriconazole to fluconazole in 600 men and women (the number of deaths was not stated) with cancer who had undergone a transplantation of their bone marrow after high‐dose chemotherapy that suppresses their immune system. The treatment was given to prevent fungal infections.

All studies were sponsored by the manufacturer of the study drug, voriconazole.

Key results 

This review found that voriconazole was inferior to liposomal amphotericin B for treatment of suspected fungal infections. More patients treated with voriconazole died and a claimed benefit in terms of fewer new fungal infections disappeared when we included patients that had been excluded without good reason from the analyses presented in the published article. We also found that voriconazole has not been compared with amphotericin B when given under optimal conditions for the treatment of invasive aspergillosis, and that voriconazole was no better than fluconazole in patients undergoing a bone marrow transplantation for preventing invasive fungal infections or for extending the time patients survive without a fungal infection.

Quality of the evidence 

The first and second trial were seriously misleading. The first trial analysed the results of the study in a different way from that originally planned, which favoured the study drug voriconazole. The second study compared voriconazole to a drug (liposomal amphotericin B) that was given at substandard dose, which means the results of the study are not meaningful. The third study should have presented how many patients died but did not.

Author(s)

Karsten Juhl Jørgensen, Peter C Gøtzsche, Christina S Dalbøge, Helle Krogh Johansen

Reviewer's Conclusions

Authors' conclusions

Implications for practice

Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of neutropenic cancer patients and should be the preferred therapy. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions. When voriconazole was compared to fluconazole for prophylaxis of fungal infections in patients treated with allogeneic stem cell transplantation, they had similar effects.

Implications for research

There is a need for a trial in patients with aspergillosis that compares voriconazole with either a lipid formulation of amphotericin B or with conventional amphotericin B given under optimal conditions, that is with premedication and replacement of electrolytes including using salt water.

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