Background
Methods
Registry
Search strategy
Selection criteria
Data extraction and outcomes
Quality appraisal
Geometry of the network
Statistical analysis
Results
Characteristics and quality appraisal of included studies
References | Study design, country | Patient population | Allo-HSCT percentage | Interventions and sample sizes (n) | Outcomes | ||
---|---|---|---|---|---|---|---|
A | B | C | |||||
Boogaerts 2001 [17] | Open, multicenter, randomized, controlled clinical trial, multi-countries (North America, Europe and Oceania) | Age ≥ 18, hematologic cancer with intensive myelosuppressive cytotoxic therapy or auto-HSCT support. | 0 | Itraconazole 200 mg iv. q12h for the first 48 h, followed by 200 mg iv. qd from days 3 to 14. From day 15, 400 mg/d po (n = 179). | C-AmB 0.7–1.0 mg/kg iv. qd (n = 181) | / | ①②③ |
Caselli 2012 [18] | Multicentre, randomized, controlled trial, Italy | Age ≤ 18, with at least one of the following features: AML, early relapse of ALL, ongoing auto-HSCT with bone marrow as the source of the stem cells, a neutropenic score ≥5. | 0 | L-AmB 3 mg/kg iv. qd (n = 25) | Caspofungin at a LD of 70 mg/m2 iv. on day 1, then 50 mg/m2 iv. qd (n = 31) | / | ③ |
Age ≤ 18, without other features mentioned above. | 0 | L-AmB 3 mg/kg iv. qd (n = 15) | Caspofungin at a LD of 70 mg/m2 iv. on day 1, then 50 mg/m2 iv. qd (n = 17) | NAT(n = 16) | |||
Groll 2010 [19] | Open, prospective, randomized multicenter phase II trial, Germany | Age ≥ 18, with allo-HSCT and immunosuppression with cyclosporine. | 100% | Caspofungin at a LD of 70 mg iv. on day 1, then 50 mg iv. qd (n = 18) | L-AmB 3 mg/kg iv. qd (n = 20) | / | ①②③ |
Jadhav 2012 [20] | Randomized, multicenter trial, India | Age > 2 and < 60, with chemotherapy or BMT. | NR | L-AmB 3 mg/kg iv. qd (n = 23) | C-AmB 1 mg/kg iv. qd (n = 20) | L-AmB 1 mg/kg iv. qd (n = 22) | ①②③ |
Jeong 2016 [33] | Randomized, controlled, prospective, multicenter study, Korea | Age ≥ 18, with intensive anticancer chemotherapy for acute leukemia, highly aggressive lymphoma, or other hematological malignancies. | 0 | Micafungin 100 mg iv. qd (n = 73) | Itraconazole200 mg iv. bid on Day 1 and 2, then 200 mg iv. qd (n = 75) | / | ①③ |
Maertens 2010 [21] | Prospective, randomized, double-blind study, multi-countries (North America and Europe) | Age > 2 and < 17, with allo-HSCT or chemotherapy for a relapse of AML or ALL. | 40.9% | Caspofungin 70 mg/m2 LD iv. on Day 1, then 50 mg/m2 iv. qd (maximum 70 mg/d) plus placebo corresponding to L-AmB (n = 15) | L-AmB 3 mg/kg iv. qd plus placebo corresponding to caspofungin (n = 7) | / | ①③ |
Age > 2 and < 17, without allo-HSCT or chemotherapy for a relapse of AML or ALL. | 0 | Casfofungin 70 mg/m2 LD iv. on Day 1, then 50 mg/m2 qd (maximum 70 mg/d) plus placebo corresponding to L-AmB (n = 41) | L-AmB 3 mg/kg iv. qd plus placebo corresponding to Caspofungin (n = 18) | / | |||
Meunier 1989 [22] | Multicenter Randomized trial, multi-countries (Europe) | Age > 15. | NR | AmB 1.2 mg/kg iv. qod or 0.6 mg/kg iv. qd (n = 57) | NAT (n = 51) | / | ①②③ |
Age ≤ 15. | NR | AmB 1.2 mg/kg iv. qod or 0.6 mg/kg iv. qd (n = 11) | NAT (n = 13) | / | |||
Oyake 2015 [23] | open-label, randomized, multicenter, comparative trial, Japan | Age ≥ 16. | 2.0% | Micafungin 150 mg iv. qd (n = 49) | Voriconazole at a LD of 6 mg/kg iv. bid on day 1 followed by 4 mg/kg iv. bid (n = 45) | / | ①②③ |
Prentice 1997 [24] | Prospective, open-label, randomized, multicenter trial, multi-countries (Europe) | Adult patients. | NR | AmB 1 mg/kg iv. qd (n = 39) | L-AmB 3 mg/kg iv. qd (n = 47) | L-AmB 1 mg/kg iv. qd (n = 47) | ③ |
Pediatric patients. | NR | AmB 1 mg/kg iv. qd (n = 61) | L-AmB 3 mg/kg iv. qd (n = 71) | L-AmB 1 mg/kg iv. qd (n = 70) | |||
Schiel 2006 [25] | Randomized, controlled multi-center trial, Germany | Age ≥ 18, with high grade hematological disorders. | 0 | NAT (n = 54) | Fluconazole 800 mg iv. at day 1, followed by 400 mg iv qd (n = 56) | / | ①③ |
Schuler 2007 [26] | Open, randomized, multicenter, parallel-group trial, Germany | Age ≥ 18, with haematological malignancy and allo-HSCT. | 100% | Itraconazole at a LD of 200 mg iv. q12h for 2 days, 200 mg iv. qd for 12 days, then solution 200 mg po. q12h (n = 26) | AmB 0.7–1 mg/kg iv. qd(n = 24) | / | ①②③ |
Age ≥ 18, with haematological malignancy and without allo-HSCT. | 0 | Itraconazole at a LD of 200 mg iv. q12h for 2 days, 200 mg iv. qd for 12 days, then solution 200 mg po. q12h (n = 55) | AmB 0.7–1 mg/kg iv. qd(n = 57) | / | |||
Viscoli 1996 [27] | Prospective, randomised, multicentre, open-label study, Italy | With cancer (including autologous or allogeneic BMT for a neoplastic disease). | 41.1% | Fluconazole 6 mg/kg iv. qd (maximum 400 mg/day) (n = 56) | AmB 0.8 mg/kg iv. qd (n = 56) | / | ①②③ |
Walsh 1999 [28] | Randomized, double-blind, multicenter trial, United states | Age > 2 and < 80, with chemotherapy for leukemia, lymphoma, or other cancers, or with BMT or peripheral HSCT. | NR | L-AmB 3 mg/kg iv. qd (n = 343) | AmB 0.6 mg/kg iv. qd (n = 344) | / | ①②③ |
Walsh 2002 [29] | Open-label, prospective, randomized, multicenter, international comparative trial, multi-countries (Europe and North America) | Age ≥ 12, with allo-HSCT or chemotherapy for relapsed leukemia. | 54.6% | Voriconazole at a LD of 6 mg/kg iv. q12h on day 1 followed by 3 mg/kg iv. q12h or 200 mg po. q12h after at least 3 days of intravenous therapy (n = 143) | L-AmB 3 mg/kg iv. qd (n = 141) | / | ①②③ |
Age ≥ 12, without allo-HSCT or chemotherapy for relapsed leukemia. | 0 | Voriconazole at a LD of 6 mg/kg iv. q12h on day 1 followed by 3 mg/kg iv. q12h or 200 mg po. q12h after at least 3 days of intravenous therapy (n = 272) | L-AmB 3 mg/kg iv. qd (n = 281) | / | |||
Walsh 2004 [30] | Prospective, double-blind study, multi-countries (North America, South America, Europe, Asia and Oceania) | Age ≥ 16, with allo-HSCT or chemotherapy for relapsed leukemia. | 28.0% | Caspofungin 70 mg iv. LD on Day 1, then 50 mg iv. qd plus placebo corresponding to L-AmB | L-AmB 3 mg/kg iv. qd plus placebo corresponding to caspofungin | / | ①③ |
Age ≥ 16, without allo-HSCT or chemotherapy for relapsed leukemia. | 0 | Caspofungin 70 mg iv. LD on Day 1, then 50 mg qd plus placebo corresponding to L-AmB | L-AmB 3 mg/kg iv. qd plus placebo corresponding to caspofungin | / | |||
Wang 2007 [31] | Open, randomized, controlled trial, China | With immunosuppression, long term use of glucocorticoid or neutropenia after radiotherapy and chemotherapy. | 41.7% | Caspofungin at a LD of 70 mg iv. on day 1, then 50 mg iv. qd (n = 32) | L-AmB 3 mg/kg iv. qd (n = 28) | / | ①③ |
Wingard 2000 [32] | Randomized, double-blind comparative Trial, United States | Age > 2. | 15.3% | L-AmB 3 mg/kg iv. qd (n = 85) | ABLC 5 mg/kg iv. qd (n = 78) | / | ①②③ |
Pairwise meta-analysis
Comparison, No. of studies | All-cause mortality | Fungal infection-related mortality | Treatment response | ||||||
---|---|---|---|---|---|---|---|---|---|
RR (95% CI) | I2
| N | RR (95% CI) | I2
| N | RR (95% CI) | I2
| N | |
Itraconazole vs AmB, 2 RCTs | 0.88 (0.57, 1.36) | 0 | 522 | 0.61 (0.14, 2.56) | 0 | 522 | 1.33 (1.10, 1.61) | 0 | 522 |
L-AmBa vs Caspofungin, 6 RCTs | 1.43 (0.98, 2.08) | 0 | 1274 | / | / | / | 0.97 (0.87, 1.08) | 0 | 1362 |
L-AmBa vs NAT, 1 RCT | / | / | / | / | / | / | 0.91 (0.67, 1.25) | / | 31 |
Caspofungin vs NAT, 1 RCT | / | / | / | / | / | / | 1.08 (0.86, 1.34) | / | 33 |
AmB vs Fluconazole, 1 RCT | 0.67 (0.12, 3.84) | / | 112 | / | / | / | 0.88 (0.69, 1.12) | / | 112 |
AmB vs NAT, 1 RCT | 0.74 (0.36, 1.51) | / | 132 | 0.10 (0.01, 1.91) | / | 132 | 1.30 (0.98, 1.72) | / | 132 |
Micafungin vs Voriconazole, 1 RCT | 2.76 (0.12, 66.07) | / | 94 | / | / | / | 1.05 (0.77, 1.42) | / | 94 |
NAT vs Fluconazole, 1 RCT | 0.35 (0.01, 8.30) | / | 110 | / | / | / | 0.89 (0.65, 1.22) | / | 110 |
Voriconazole vs L-AmBa, 1 RCT | 1.34 (0.81, 2.22) | / | 837 | 0.51 (0.05, 5.59) | / | 837 | 0.85 (0.69, 1.06) | / | 837 |
Micafungin vs Itraconazole, 1 RCT | 0.77 (0.28, 2.11) | / | 148 | / | / | / | 1.12 (0.87, 1.46) | / | 148 |
L-AmBa vs AmB, 3 RCTs | 0.73 (0.46, 1.17) | 0 | 730 | 0.36 (0.12, 1.13) | / | 687 | 1.09 (0.91, 1.31) | 0.36 | 948 |
L-AmBa vs L-AmBb, 2 RCTs | 0.96 (0.22, 4.24) | / | 45 | / | / | / | 1.03 (0.82, 1.29) | 0.14 | 280 |
AmB vs L-AmBb, 2 RCTs | 0.73 (0.14, 3.95) | / | 42 | / | / | / | 0.85 (0.68, 1.06) | 0 | 259 |
L-AmBa vs ABLC, 1 RCT | 0.42 (0.15, 1.15) | / | 163 | 0.31 (0.03, 2.88) | / | 163 | 1.20 (0.80, 1.80) | / | 163 |
Network meta-analysis
All-cause mortality
ABLC | AmB | Caspofungin | Fluconazole | Itraconazole | L-AmBa
| L-AmBb
| Micafungin | NAT | Voriconazole |
---|---|---|---|---|---|---|---|---|---|
2.13 (0.25, 15.53) | |||||||||
4.00 (0.36, 30.31) | 2.00 (0.29, 9.16) | ||||||||
0.82 (0.03, 13.01) | 0.44 (0.04, 3.16) | 0.24 (0.01, 2.79) | |||||||
2.23 (0.19, 18.54) | 1.06 (0.32, 2.75) | 0.55 (0.08, 4.32) | 2.38 (0.27, 32.66) | ||||||
2.30 (0.13, 30.41) | 1.00 (0.13, 8.32) | 0.53 (0.05, 6.77) | 2.51 (0.14, 58.87) | 0.97 (0.10, 10.44) | |||||
2.92 (0.51, 17.19) | 1.44 (0.43, 4.65) | 0.72 (0.24, 3.10) | 3.17 (0.38, 54.22) | 1.34 (0.31, 7.65) | 1.45 (0.18, 10.99) | ||||
2.28 (0.10, 27.64) | 1.10 (0.11, 5.97) | 0.53 (0.04, 5.76) | 2.53 (0.16, 43.72) | 1.03 (0.17, 4.87) | 1.14 (0.05, 15.78) | 0.72 (0.07, 5.08) | |||
1.57 (0.13, 26.34) | 0.79 (0.18, 4.60) | 0.41 (0.05, 5.77) | 1.93 (0.13, 34.81) | 0.74 (0.15, 6.87) | 0.73 (0.06, 12.62) | 0.55 (0.09, 4.65) | 0.69 (0.09, 14.59) | ||
2.49 (0.29, 24.91) | 1.12 (0.23, 8.07) | 0.58 (0.12, 6.07) | 2.68 (0.24, 74.04) | 1.08 (0.20, 11.04) | 1.16 (0.12, 15.57) | 0.78 (0.22, 4.00) | 1.03 (0.14, 18.98) | 1.49 (0.13, 15.91) |