Abstract

Background

Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or empirically to patients with persistent fever.

Objectives

To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia.

Search methods

We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles.

Selection criteria

Randomised clinical trials comparing fluconazole with amphotericin B.

Data collection and analysis

The two review authors independently assessed trial eligibility and risk of bias, and abstracted data.

Main results

Seventeen trials (3798 patients, 381 deaths) were included. In two large three‐armed trials, results for amphotericin B were combined with results for nystatin in a 'polyene' group. Because nystatin is an ineffective drug in these circumstances, this approach creates a bias in favour of fluconazole. Furthermore, most patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. There was overlap among the 'polyene' trials but we were unable to obtain any information from the trial authors or from Pfizer, the manufacturer of fluconazole, to clarify these issues. There were no significant differences in effect between fluconazole and amphotericin B, but the confidence intervals were wide. More patients dropped out of the study when they received amphotericin B, but as none of the trials were blinded decisions on premature interruption of therapy could have been biased. Furthermore, amphotericin B was not given under optimal circumstances, with premedication to reduce infusion‐related toxicity, slow infusion, and with fluid, potassium and magnesium supplements to prevent nephrotoxicity. The major harms were hepatic impairment and gastrointestinal adverse effects with fluconazole and infusion‐related toxicity, renal impairment and gastrointestinal adverse effects with amphotericin B. For the 2011 and 2014 updates no additional trials were identified for inclusion.

Authors' conclusions

Amphotericin B has been disfavoured in several of the trials through their design or analysis, or both. Since intravenous amphotericin B is the only antifungal agent for which an effect on mortality has been shown, and since it is considerably cheaper than fluconazole, it should be the preferred agent.

Author(s)

Helle Krogh Johansen, Peter C Gøtzsche

Abstract

Plain language summary

Prevention of fungal infections in cancer patients with amphotericin B or fluconazole

Cancer patients treated with chemotherapy or who receive a bone marrow transplant have an increased risk of acquiring fungal infections. Such infections can be life‐threatening. Antifungal drugs are therefore often given prophylactically to such patients, or when they have a fever. The review could not detect a difference in effect between amphotericin B and fluconazole but several of the trials were designed or analysed in a way that disfavoured amphotericin B, which is the only antifungal drug that has been shown to have an effect on mortality.

Author(s)

Helle Krogh Johansen, Peter C Gøtzsche

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

The relative merits of fluconazole compared with amphotericin B cannot be judged based on the available trials. Intravenous amphotericin B should therefore be preferred for prophylactic or empirical antifungal therapy in cancer patients with neutropenia as it is the only antifungal agent for which an effect on mortality has been shown.

Implications for research 

A large trial, with several hundred deaths, that compares fluconazole with intravenous amphotericin B, either as standard drug or as a lipid soluble form to reduce the adverse effects, could be worthwhile. Given the many problems with the fluconazole trials performed previously, such a trial should be planned, executed and analysed independently of sponsors. To reduce the risk of biased meta‐analyses, we recommend that trial investigators keep copies of their data.

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