H K Johansen1, P C Gøtzsche. 1. The Nordic Cochrane Centre, Rigshospitalet, Dept. 7112, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. hkj@cochrane.dk
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 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 STRATEGY: MEDLINE and Cochrane Library (November 2001). Letters, abstracts, and unpublished trials. The industry and authors were contacted. SELECTION CRITERIA: Randomised trials comparing fluconazole with amphotericin B. 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 by both authors independently. MAIN RESULTS: Sixteen trials (3760 patients, 341 deaths) were included. In 3 large 3-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. It was unclear whether there was overlap among the "polyene" trials. We were unable to obtain any information to clarify these issues from the trial authors or from Pfizer, the manufacturer of fluconazole. 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 rarely given under optimal circumstances, with premedication to reduce infusion-related toxicity, slow infusion, and with potassium and magnesium supplements to prevent nephrotoxicity. REVIEWER'S CONCLUSIONS: Amphotericin B had been disfavoured in several of the trials through their design or analysis. Since intravenous amphotericin B is the only antifungal agent for which there is good evidence suggesting an effect on mortality and is considerably cheaper than fluconazole, it should be preferred.
BACKGROUND: Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancerpatients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or 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 STRATEGY: MEDLINE and Cochrane Library (November 2001). Letters, abstracts, and unpublished trials. The industry and authors were contacted. SELECTION CRITERIA: Randomised trials comparing fluconazole with amphotericin B. 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 by both authors independently. MAIN RESULTS: Sixteen trials (3760 patients, 341 deaths) were included. In 3 large 3-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. It was unclear whether there was overlap among the "polyene" trials. We were unable to obtain any information to clarify these issues from the trial authors or from Pfizer, the manufacturer of fluconazole. 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 rarely given under optimal circumstances, with premedication to reduce infusion-related toxicity, slow infusion, and with potassium and magnesium supplements to prevent nephrotoxicity. REVIEWER'S CONCLUSIONS:Amphotericin B had been disfavoured in several of the trials through their design or analysis. Since intravenous amphotericin B is the only antifungal agent for which there is good evidence suggesting an effect on mortality and is considerably cheaper than fluconazole, it should be preferred.