Routine versus selective antifungal administration for control of fungal infections in patients with cancer

Peter C Gøtzsche; Helle Krogh Johansen

doi:10.1002/14651858.CD000026.pub2

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Analysis 1.1

Comparison 1 Antifungals versus placebo or no treatment, Outcome 1 Death.

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Analysis 1.2

Comparison 1 Antifungals versus placebo or no treatment, Outcome 2 Death related to fungal infection.

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Analysis 1.3

Comparison 1 Antifungals versus placebo or no treatment, Outcome 3 Invasive infections.

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Analysis 1.4

Comparison 1 Antifungals versus placebo or no treatment, Outcome 4 Colonisation.

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Analysis 1.5

Comparison 1 Antifungals versus placebo or no treatment, Outcome 5 Use of escape drug.

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Table 1. Harms

Trial	Trial drug	Number of patients	Harms
EORTC 1989	amphotericin B	80 versus 77	Treatment discontinuations: 6 pts on trial drug (infusion‐related toxicity, allergic reactions); Nephrotoxicity: 8 versus 3, none required dialysis and renal function restored later; Hypokalaemia: 33 versus 16
Goldstone 1994	amphotericin B	64 versus 69	Treatment discontinuations: 4 on trial drug (chills, rigour, hypotension, rash and bronchospasm); Elevated liver function tests: 26 versus 32; Nephrotoxicity: 1 on trial drug that did not require withdrawal of therapy
Kelsey 1999	amphotericin B	74 versus 87	Treatment discontinuations: 5 on trial drug, 1 on placebo because of immediate reactions; Nephrotoxicity: 9 versus 6; Hypokalaemia: 1 versus 0; Clinical adverse events were very similar in the two groups
Penack 2006.	amphotericin B	75 versus 57	Treatment discontinuations: 2 (1 skin rash, 1 chills) versus 0; Other harms: "no differences in ... liver function tests, renal function parameters and hypokalaemia"
Perfect 1992	amphotericin B	91 versus 91	More infusion‐related harms on active drug, but no data provided; No significant differences in renal function, hepatic enzymes or electrolytes (no data provided)
Pizzo 1982	amphotericin B	18 versus 16	Treatment discontinuations: none; Rash: 2 versus 1; Azotaemia: 1 versus 0; liver enzyme elevations: 2 versus 3; Electrolyte abnormalities: 18 versus 16
Riley 1994	amphotericin B	17 versus 18	Treatment discontinuations: none; Renal function: no difference (P value 0.82 for blood urea, P value 0.63 for creatinine); Potassium supplements: no difference; Infusion reactions: none
Suda 1980	amphotericin B	39 versus 31	Article is in Japanese
Tollemar 1993	amphotericin B	42 versus 42	Treatment discontinuations: 4 versus 0 for infusion reactions; Potassium supplementation: no difference; Renal function: no useful data, but only small changes reported, compared to normal ranges
Fukuda 1994	fluconazole	37 versus 26	Article is in Japanese
Goodman 1992	fluconazole	179 versus 177	Treatment discontinuations: 1 on trial drug, 2 on placebo for clinical side effects, and 17 versus 11 for elevated liver function tests; in 7 versus 3, hepatic dysfunction contributed to death; Graft‐versus‐host disease or organ failure: 44 versus 24 deaths; Nausea: 13 versus 9; Skin rash: 9 versus 9; Eosinophilia in 6 versus 0
Kern 1998	fluconazole	36 versus 32	Bacteriaemia: 15 versus 7; Other harms similar: 5 versus 6 elevations in transaminases, 19 versus 17 nausea or vomiting, 3 versus 0 allergy
Rotstein 1999	fluconazole	141 versus 133	Treatment discontinuations: none reported; Elevated liver enzymes: 17 versus 19; Rash: 51 versus 59; Nausea: 106 versus 95; Vomiting: 68 versus 85
Schaffner 1995	fluconazole	76 versus 76 episodes	Treatment discontinuations: none reported; No data on harms ("no significant differences were found")
Slavin 1995	fluconazole	152 versus 148	Treatment discontinuations: 32 versus 31 for abnormal liver function; Graft‐versus‐host disease: 102 versus 85; Nausea: 33 versus 22; Seizures: 8 versus 9; Liver enzymes: no differences
Winston 1993	fluconazole	124 versus 133	Treatment discontinuations: none reported; Elevated liver enzymes: 25 versus 14; Nausea and vomiting: 9 versus 5; Rash: 13 versus 7; Other harms were similarly distributed
Yamac 1995	fluconazole	41 versus 29	Treatment discontinuations: none reported; Other harms: no data
Acuna 1981	ketoconazole	28 versus 24	No data
Benhamou 1991	ketoconazole	63 versus 62	Treatment discontinuations: 38 versus 14 (among them 2 patients with veno‐occlusive disease, 1 hepatitis, 3 skin rash in active group; none in placebo group); Severe gastrointestinal intolerance: 4 versus 7; Three‐fold greater values than normal for transaminases: 13 versus 8
Brincker 1983	ketoconazole	19 versus 19	One patient on trial drug stopped treatment because of universal exanthema
Estey 1984	ketoconazole	77 versus 73	Bacterial infections: 33 versus 24
Hansen 1987	ketoconazole	27 versus 29	Treatment discontinuations: 2 on trial drug (1 skin rash and 1 elevated liver function tests); Bacterial infections: 20% versus 15% of neutropenic episodes
Hughes 1983	ketoconazole	42 versus 22	Treatment discontinuations:1 on trial drug (nausea and anorexia); Other harms: 2 nausea and anorexia, 1 abdominal pain, 1 transient rash, all on trial drug
Palmblad 1992	ketoconazole	55 versus 61	Treatment discontinuations: 2 (elevated transaminases) versus 6 (1 elevated transaminases, 5 exanthema); Bacteriaemias: 37 versus 21
Siegel 1982a	ketoconazole	12 versus 13	No data
Brincker 1978	miconazole	15 versus 15	None ascribable to trial drug
Wingard 1987	miconazole	97 versus 111	Treatment discontinuations: 1 (pruritis and flushing) versus 2 (1 rash, 1 nausea); Severe hypotension: 2 on trial drug
Caselli 1990	itraconazole, amphotericin B, ketoconazole	30 versus 10	No data
Kaptan 2003	itraconazole	31 versus 24	Treatment discontinuations: 2 on trial drug (cardiac arrhytmia and gastric irritation); "there was a clinical impression that hypokalaemia occurred at a greater rate in patients with itraconazole"
Menichetti 1999	itraconazole	201 versus 204	Treatment discontinuations: 37 versus 27; Bacteriaemia: 47 versus 31; Elevated transaminases: 5 versus 3
Nucci 2000	itraconazole	104 versus 106	Treatment discontinuations: 3 versus 4; Skin rash: 3 versus 1; Elevated liver enzymes: 3 versus 4; Nausea: 2 on placebo
Vreugdenhil 1993	itraconazole	49 versus 49	Treatment discontinuations: 1 (nausea) versus 1 (liver function deterioration); Liver function deterioration: 28 versus 22 episodes; Renal function deterioration: 4 versus 2 episodes

Table 1. Harms

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Comparison 1. Antifungals versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	26	3902	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.81, 1.09]

1.1 Amphotericin	9	988	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.50, 0.96]
1.2 Fluconazole	7	1470	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.84, 1.30]
1.3 Ketoconazole	4	429	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.63, 1.49]
1.4 Miconazole	2	238	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.71, 1.87]
1.5 Itraconazole	4	777	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.63, 1.40]
2 Death related to fungal infection Show forest plot	23	3490	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.38, 0.71]

2.1 Amphotericin	9	988	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.26, 0.76]
2.2 Fluconazole	6	1213	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.24, 0.73]
2.3 Ketoconazole	3	304	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.55, 4.04]
2.4 Miconazole	1	208	Risk Ratio (M‐H, Fixed, 95% CI)	0.13 [0.01, 2.33]
2.5 Itraconazole	4	777	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.31, 1.56]
3 Invasive infections Show forest plot	30	4044	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.39, 0.64]

3.1 Amphotericin	8	855	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.24, 0.73]
3.2 Fluconazole	8	1539	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.27, 0.57]
3.3 Ketoconazole	7	562	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.68, 2.54]
3.4 Miconazole	2	238	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.20, 1.31]
3.5 Itraconazole	4	810	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.29, 0.97]
3.6 Itraconazole/ketoconazole/amphotericin	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Colonisation Show forest plot	22		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Amphotericin	3	378	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.33, 0.77]
4.2 Fluconazole	6	1393	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.33, 0.90]
4.3 Ketoconazole	8	626	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.51, 0.87]
4.4 Miconazole	2	238	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.37, 2.24]
4.5 Itraconazole	2	503	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.57, 1.45]
4.6 Itraconazole/ketoconazole/amphotericin	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.31, 1.04]
5 Use of escape drug Show forest plot	24		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Amphotericin	6	636	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.35, 1.03]
5.2 Fluconazole	7	1469	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.76, 1.02]
5.3 Ketoconazole	6	412	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.58, 1.44]
5.4 Miconazole	2	238	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.94, 1.46]
5.5 Itraconazole	3	712	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.57, 0.95]

Comparison 1. Antifungals versus placebo or no treatment

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