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Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials

Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer... Clinical Studies British Journal of Cancer (2012) 106, 1626–1637 & 2012 Cancer Research UK All rights reserved 0007 – 0920/12 www.bjcancer.com Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials 1,2 2,3 1,4 4,5 6 ,1,7 MC Ethier , M Science , J Beyene , M Briel , T Lehrnbecher and L Sung 1 2 Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto M5G 1X8, Ontario, Canada; Program in Health Research Methodology, McMaster University, Hamilton L8S 4L8, Ontario, Canada; Division of Infectious Diseases, The Hospital for Sick Children, Toronto M5G 1X8, Ontario, Canada; Population Genomics Program, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton L8S 4L8, 5 6 Ontario, Canada; Basel Institute for Clinical Epidemiology and Biostatistics, Basel, Switzerland; Pediatric Hematology and Oncology, University of Frankfurt, Frankfurt, Germany; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto M5G 1X8, Ontario, Canada BACKGROUND: Objectives were to compare systemic mould-active vs fluconazole prophylaxis in cancer patients receiving chemotherapy or haematopoietic stem cell transplantation (HSCT). METHODS: We searched OVID MEDLINE and the Cochrane Central Register of Controlled Trials (1948-August 2011) and EMBASE (1980-August 2011). Randomised controlled trials of mould-active vs fluconazole prophylaxis in cancer or HSCT patients were included. Primary outcome was proven/probable invasive fungal infections (IFI). Analysis was completed by computing relative risks (RRs) using a random-effects model and Mantel–Haenszel method. RESULTS: From 984 reviewed articles, 20 were included in this review. Mould-active compared with fluconazole prophylaxis significantly reduced the number of proven/probable IFI (RR 0.71, 95% CI 0.52 to 0.98; P¼ 0.03). Mould-active prophylaxis also decreased the risk of invasive aspergillosis (IA; RR 0.53, 95% confidence interval (CI) 0.37–0.75; P¼ 0.0004) and IFI-related mortality (RR 0.67, 95% CI 0.47–0.96; P¼ 0.03) but is also associated with an increased risk of adverse events (AEs) leading to antifungal discontinuation (RR 1.95, 95% CI 1.24–3.07; P¼ 0.004). There was no decrease in overall mortality (RR 1.0; 95% CI 0.88–1.13; P¼ 0.96). CONCLUSION: Mould-active compared with fluconazole prophylaxis significantly reduces proven/probable IFI, IA, and IFI-related mortality in cancer patients receiving chemotherapy or HSCT, but increases AE and does not affect overall mortality. (PROSPERO Registration: CRD420111174) British Journal of Cancer (2012) 106, 1626–1637. doi:10.1038/bjc.2012.147 www.bjcancer.com & 2012 Cancer Research UK Keywords: antifungal; prophylaxis; fluconazole; infections Cancer patients receiving intensive chemotherapy or undergoing echinocandins such as caspofungin and micafungin, and ampho- haematopoietic stem cell transplantation (HSCT) are at an tericin have coverage that extends to yeasts and moulds. However, increased risk of invasive fungal infections (IFI); both yeasts and each of these agents may have specific downsides including moulds contribute to IFI in these populations (Mahfouz and toxicity, potential for drug interactions and considerable costs. Anaissie, 2003). IFI are associated with considerable morbidity and Previous randomised trials have shown the benefits of mortality. Although invasive aspergillosis (IA) has decreased in fluconazole prophylaxis when compared with placebo in patients recent years (Pagano et al, 2010), mortality remains unacceptably receiving chemotherapy and undergoing HSCT (Goodman et al, high. As a result, emphasis has been placed on prevention of IFI 1992; Slavin et al, 1995; Rotstein et al, 1999). However, individual using prophylactic strategies. trials comparing mould-active prophylaxis to fluconazole have Choices for systemic antifungal prophylaxis include fluconazole yielded inconsistent results with most studies failing to show a and agents with activity against moulds. Fluconazole is inexpen- reduction in proven or probable IFI (Wingard et al, 2010). sive and in general, well tolerated. However, it lacks activity against Consequently, there are conflicting recommendations for anti- moulds, in particular against Aspergillus spp. In contrast, newer fungal prophylaxis from published guidelines (Cornely et al, 2009; broad-spectrum azoles such as voriconazole and posaconazole, Freifeld et al, 2011), which has led to variability in clinical practice (Lehrnbecher et al, 2009). Although there are many randomised trials which assessed the efficacy of antifungal prophylaxis, most were underpowered *Correspondence: Dr L Sung; E-mail: lillian.sung@sickkids.ca to detect a significant difference in the incidence of proven or Received 7 November 2011; revised 6 March 2012; accepted 22 March probable IFI or all-cause mortality. We hypothesised that 2012 Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al including all available studies that compared mould-active vs Outcomes fluconazole prophylaxis would improve the ability to determine The primary outcome was proven or probable IFI. IFI were whether mould-active agents are associated with fewer proven or re-classified using the revised EORTC/MSG criteria when sufficient probable IFI and whether these agents are associated with a data were available and authors used other definitions (De Pauw survival benefit. The primary objective of this review was to et al, 2008). When re-classification was not possible, the study was determine whether mould-active prophylaxis reduces the inci- not included in the analysis of this outcome. A secondary outcome dence of proven or probable IFI, when compared with fluconazole. was IA that was defined as culture-proven Aspergillus or The secondary objectives were to determine whether mould-active Aspergillus diagnosed by microscopic examination (De Pauw prophylactic strategies, when compared with fluconazole, are et al, 2008). The time period for IFI and IA observation was during associated with a reduction in: (1) incidence of IA; (2) adverse the study period, which varied across studies. Other secondary events (AE) requiring discontinuation or modification of outcomes were IFI- and IA-related mortality, all-cause mortality antifungal prophylaxis; (3) number of IFI- and IA-related deaths; and adverse events leading to discontinuation or modification and (4) all-cause mortality. of study drug. The time period for observation of mortality was 3 months. We did not examine possible IFI as there was considerable inconsistency as to how this outcome was defined. METHODS The reporting of this meta-analysis follows the recommendations Data collection process of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (Moher et al, 2009). Methods of the Two reviewers (MCE and MS) independently abstracted data analysis and inclusion criteria were specified in advance from included trials using a standardised data collection form. and registered in the PROSPERO registry of systematic reviews Disagreements were resolved by discussion between the two (Ethier, 2011). reviewers; if no agreement could be reached, it was pre-specified that a third author (LS) would arbitrate. Corresponding authors were contacted to retrieve additional data if needed. Eligibility criteria The following information was extracted: (1) study character- istics (recruitment period, number of subjects, follow-up period, Randomised controlled trials comparing systemic mould-active to country where study performed, whether study was multicenter, fluconazole prophylaxis were eligible. Any of the following mould- concurrent antibiotic prophylaxis, definitions for IFI, criteria for active agents were included as long as they were administered starting and stopping prophylaxis); (2) characteristics of trial systemically: amphotericin B (conventional and lipid formula- participants (population, diagnosis, age, gender); (3) intervention tions), caspofungin, micafungin, anidulafungin, posaconazole, and comparison (name of drug, dose, route, duration, frequency); itraconazole, voriconazole, or ketoconazole. Inclusion criteria and (4) outcomes. were: (1) randomisation between systemic mould-active and fluconazole prophylaxis; and (2) patients of any age receiving chemotherapy for cancer or undergoing HSCT. We excluded Risk of bias in individual studies (1) studies in which more than one systemic prophylactic anti-fungal agent was given in one of the study arms; (2) studies that did not To assess the risk of bias, included articles were examined by two report any of the primary or secondary outcomes; and (3) studies of reviewers (MCE and MS) for: (1) generation of sequence allocation; pre-emptive or empiric therapy or anti-fungal treatment. There were (2) allocation concealment; (3) blinding; (4) incomplete outcome no restrictions by language or by publication status. data; and (5) intention-to-treat (ITT) analysis. Definitions/criteria of these items were derived from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins and Green, 2009). Information sources and search details We performed an electronic search of OVID MEDLINE (from 1948 Statistical analysis to August 2011), EMBASE (from 1980 to August 2011), and The Cochrane Central Register of Controlled Trials (CENTRAL; until The meta-analysis was performed by computing relative risks the third quarter of 2011). Searches were last updated 24 August (RRs) using a random-effects model as heterogeneity between 2011. We also reviewed the reference lists of relevant articles and trials was expected. We followed the ITT principle when we reviews as well as trials registered on the ClinicalTrials.gov calculated summary RRs with 95% confidence intervals (CI). The website. We searched for conference proceedings from 2005 to Mantel–Haenszel method was chosen as the event rates were 2011 using the Web of Science (version 4.10) as well as abstracts relatively low across all outcomes. We considered P-valueso0.05 presented within the last 2 years at annual meetings of the statistically significant. Synthesis was performed using Review American Society of Hematology and American Society of Clinical Manager (Version 5.1, The Cochrane Collaboration, 2011, http:// Oncology. ims.cochrane.org/revman/download). Meta-regression also was We used the following search terms in both indexed and text performed in addition to stratified analyses using SAS-PC software word forms to search all databases: fluconazole, Aspergillus or (version 9.2; SAS Institute, Cary, NC, USA). mycoses, prevention or prophylaxis, neoplasm or SCT or Sub-group analyses defined a priori were performed to neutropenia, with appropriate limits to identify randomised investigate the effects of age (children vs adults), study population controlled trials (Appendix Table A1 for full search strategy). (HSCT vs chemotherapy), drug used in the experimental Two reviewers (MCE and MS) assessed the title and abstract of comparison group (amphotericin vs mould-active azoles vs each reference identified by the search and applied the eligibility echinocandins), and dose of fluconazole (X400 mg per day vs criteria. For potentially relevant articles, the full article was o400 mg per day). We excluded studies that included both obtained and assessed by both authors independently. Final chemotherapy and HSCT patients from the study population sub- inclusion of studies in the meta-analysis was determined by group analysis. We also examined subgroups by blinding and ITT agreement of both reviewers. If consensus could not be reached, analysis. Outcomes identified for sub-group analyses were proven/ disagreements were resolved by a third study author (LS). probable IFI, IA, IFI-, and IA-related mortality, overall mortality Agreement between reviewers was evaluated by using the kappa and AEs requiring antifungal treatment discontinuation or statistic. modification. & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Concern has been raised about the effectiveness of itraconazole trials and serum beta-D-glucan testing in one trial (Ito et al, 2007a; capsule to prevent IFD (Prentice et al, 2006) and at least two sets of Ullmann et al, 2007; Wingard et al, 2010). guidelines have recommended against its use as prophylaxis Risk of bias assessment is presented in Table 2. The majority of (Walsh et al, 2008; Maertens et al, 2011). Consequently, we also studies did not provide adequate information on sequence conducted a sensitivity analysis excluding the two studies that used allocation and allocation concealment. Only 4 out of 20 (20%) of itraconazole capsules. There also has been concerns about whether the studies were blinded and 6 out of 20 (30%) performed an ITT doses of itraconazole solution o400 mg per day is effective analysis. (Glasmacher et al, 2003) and consequently, we conducted a second The analysis of the primary outcome, which was proven or sensitivity analysis in which we deleted studies that used doses probable IFI, encompassed 2385 (mould-active group) and 2417 lower than this threshold amount. (fluconazole group) patients, in 18 studies. When data from all 18 Heterogeneity was initially inspected graphically (forest plot) studies that reported on our primary outcome were pooled, and assessed statistically using the I statistic and by performing a mould-active compared with fluconazole prophylaxis significantly test for heterogeneity. reduced the risk of IFI (RR 0.71, 95% CI 0.52–0.98; P¼ 0.03), with We assessed the possibility of publication bias by examining moderate heterogeneity (I ¼ 33%, P¼ 0.11) as illustrated in funnel plots for asymmetry (Sutton et al, 2000). Table 3 and Figure 2. Mould-active prophylaxis, when compared with fluconazole prophylaxis, decreased the risk of IA (RR 0.53, 95% CI 0.37–0.75) RESULTS and IFI-related mortality (RR 0.67, 95% CI 0.47–0.96). However, mould-active prophylaxis was significantly associated with more A total of 984 titles and abstracts were reviewed (Figure 1); 20 were adverse events leading to antifungal prophylaxis discontinuation retrieved for detailed evaluation (Bodey et al, 1994; Annaloro et al, or modification when compared with fluconazole prophylaxis (RR 1995; Morgenstern et al, 1999a; Huijgens et al, 1999b; Timmers 1.95, 95% CI 1.24–3.07). Importantly, mould-active prophylaxis et al, 2000b; Wolff et al, 2000b; Koh et al, 2002a; Glasmacher et al, did not significantly influence overall mortality (RR 1.0, 95% CI 2003; Winston et al, 2003; Marr et al, 2004; van Burik et al, 2004; 0.88–1.13). Funnel plots were reviewed for each of the study Choi et al, 2005; Oren et al, 2006b; Cornely et al, 2007; Ito et al, outcomes. No apparent asymmetry was seen by visual assessment 2007b; Ullmann et al, 2007; Hiramatsu et al, 2008b; Sawada et al, (data not shown). 2009a; Ota et al, 2010; Wingard et al, 2010) and all 20 (19 full-text The results from the subgroup analyses for 4 of our 5 pre- articles and one conference abstract (Ota et al, 2010)) satisfied specified outcomes are presented in Table 4 and Appendix eligibility criteria and were included in the final meta-analysis. Table A3. Subgroup analysis by age was not possible as only one The kappa statistic for study inclusion was 1.0, reflecting perfect study included children only. There was no evidence for a agreement. difference in the effect of mould-active vs fluconazole prophylaxis Demographics of the 20 included studies are presented in for any of the outcomes. However, the beneficial effect of mould- Table 1. A total of 5725 patients were included in this review with active prophylaxis appeared qualitatively greater in studies of ages ranging from 0.6 to 82 years. Trials were performed in Asia other azoles and echinocandins in comparison with amphotericin (n¼ 7), Europe (n¼ 5), North America (n¼ 5), and internationally B formulations. There was no evidence that the effect of mould- (n¼ 3). Half of the studies were multi-centred (10 out of 20, active prophylaxis differed by blinding status or application of the 50.0%). The patient populations were HSCT (n¼ 14) and ITT principle (Appendix Table A2). The results from the meta- chemotherapy (n¼ 6). Children were included in four trials but regression are presented in Appendix Table A4 and are consistent only one trial comprised of children only. Antibiotic prophylaxis with the results from the sub-group analysis. was recommended in 8 out of 20 (40%) of trials. Study regimens Appendix Table A5 illustrates the sensitivity analyses that included amphotericin B formulations (n¼ 4), micafungin (n¼ 3), removed the two studies of itraconazole capsule prophylaxis and posaconazole (n¼ 2), voriconazole (n¼ 1), and itraconazole the three studies that used oral itraconazole solution doses (n¼ 10). All studies of echinocandins consisted of micafungin. o400 mg per day. The removal of these studies did not impact Fungal prophylaxis was started either with the initiation of the results, with the exception of proven or probably IFI which was chemotherapy (n¼ 18) or at the onset of neutropenia (n¼ 1; no longer significant after removing the three studies that used Sawada et al, 2009a), and was not available for one study (Choi oral itraconazole solution doses o400 mg per day. et al, 2005). Routine galatomannan testing was performed in two DISCUSSION Potentially eligible studies We found that in patients with cancer receiving chemotherapy or identified by the search HSCT, mould-active prophylaxis when compared with fluconazole strategy prophylaxis was associated with a clinically relevant reduction in (n = 984) proven or probable IFI, IA and IFI-related mortality. However, Excluded by review of title and abstract (n = 964) mould-active prophylaxis was also associated with a significantly Did not fulfill inclusion / exclusion increased risk of adverse events requiring discontinuation or criteria modification of therapy and did not affect overall mortality. (n = 750) These results are in keeping with those from a previous review Duplicate publication (n = 214) comparing mould-active to fluconazole prophylaxis that was Full articles retrieved for conducted as a sub-group analysis of a large review; this review detailed evaluation included studies published up to 2007 (Robenshtok et al, 2007). (n = 20) Similar to our study, that review found that mould-active prophylaxis significantly reduced documented IFI, IA, and IFI- related mortality, and did not impact on all-cause mortality. Our Studies included in meta- results provide important new information since six new trials analysis comparing fluconazole to systemic mould-active prophylaxis were (n = 20) added (Choi et al, 2005; Ito et al, 2007a; Hiramatsu et al, 2008a; Figure 1 Flow diagram of trial identification and selection. Sawada et al, 2009b; Ota et al, 2010; Wingard et al, 2010), which British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table 1 Characteristics of included trials that compare fluconazole vs mould-active antifungal prophylaxis Surro- Multi- gate Study author Pub year centre N Population Mould-active dose Fluconazole dose Prophylaxis end testing 1  1 Bodey et al, 1994 1994 No 77 Hem malignancy CAB 0.17 mg kg per dose 400 mg per dose PO/IV ANC41000 ml or 8 No IV TID OD weeks Annaloro et al, 1995 No 59 HSCT (auto, allo) Itraconazole 400 mg per dose 300 mg per dose PO OD Neutropenia resolution No 1995 PO OD Huijgens et al, 1999 No 202 Hem malignancy, HSCT Itraconazole 100 mg per dose 50 mg per dose PO BID ANC4500 ml No 1999a (auto) PO BID 1  1 Morgenstern 1999 Yes 581 Hem malignancy, HSCT Itraconazole 2.5 mg kg per 100 mg per dose PO OD ANC41000 ml  7 No et al, 1999b (auto, allo) dose PO BID days Timmers et al, 2000 No 24 Hem malignancy, HSCT Amphotericin B colloidal 200 mg per dose PO OD ANC4500 ml No 2000a (auto, allo) dispersion 2 mg kg per dose IV OD 1  1 Wolff et al, 2000 Yes 355 HSCT (auto, allo) CAB 0.2 mg kg per dose IV 400 mg per dose PO/IV ANC4500 ml No 2000a OD OD 1  1 Koh et al, 2002b 2002 No 186 HSCT (auto, allo) CAB 0.2 mg kg per dose IV 200 mg per dose PO OD ANC4500 ml  3 No OD days Winston et al, 2003 Yes 138 HSCT (allo) Itraconazole 200 mg per dose 400 mg per dose IV Dþ 100 No 2003 IV BID 4 then 200 mg per OD 14 then 400 mg dose IV OD 12 then 200 mg per dose PO OD until per dose PO BID until Dþ 100 Dþ 100 Marr et al, 2004 2004 No 299 HSCT (allo) Itraconazole 2.5 mg kg per 400 mg per dose PO/IV Dþ 120–180 days No dose PO TID or 200 mg per OD dose IV OD van Burik et al, 2004 Yes 882 HSCT (auto, allo) Micafungin 50 mg per dose IV 400 mg per dose IV OD ANCX500 ml  5 No 2004 OD days or Dþ 42 Choi et al, 2005 2005 No 78 HSCT (allo) Itraconazole 200 mg per dose 200 mg per dose PO OD NS No PO OD 1  1 Glasmacher et al, 2006 Yes 494 Hem malignancy Itraconazole 5 mg kg per 400 mg per dose PO/IV ANC41000 ml or 8 No 2006 dose PO BID OD weeks Oren et al, 2006a 2006 No 195 Hem malignancy, HSCT Itraconazole 200 mg per dose 400 mg per dose PO/IV Neutropenia resolution or No (auto, allo) PO/IV BID OD 8 weeks Cornely et al, 2007 Yes 544 Hem malignancy Posaconazole 200 mg per 400 mg per dose PO/IV Neutropenia resolution or No 2007 dose PO/IV BID OD 12 weeks Ito et al, 2007a 2007 Yes 209 Hem malignancy Itraconazole 200 mg per dose 200 mg per dose PO OD ANC 41000 ml or Yes PO OD leukocytesX2 ml Ullmann et al, 2007 Yes 600 GVHD Posaconazole 200 mg per 400 mg per dose PO OD 112 days Yes 2007 dose PO TID Hiramatsu et al, 2008 No 100 HSCT (auto, allo) Micafungin 150 mg per dose IV 400 mg per dose IV OD ANC4500 ml 5or No 2008a OD Dþ 42 1  1  1 Sawada et al, 2009 Yes 107 Hem malignancy, HSCT Micafungin 2 mg kd per 10 mg kg per dose IV ANC4500 ml No 2009b (allo/auto) dose IV OD OD Ota et al, 2010 2010 No 73 HSCT (auto, allo) Itraconazole 200 mg per dose 400 mg per dose PO/IV Dþ 28 No PO/IV OD OD Wingard et al, 2010 Yes 600 HSCT (allo) Voriconazole 200 mg per dose 400 mg per dose PO OD Dþ 100 Yes 2010 PO BID Abbreviations: allo¼ allogeneic; ANC¼ absolute neutrophil count; auto¼ autologous; BID¼ twice daily; CAB¼ conventional amphotericin B; D¼ day of HSCT; GVHD¼ graft- vs-host disease; Hem¼ haematological; HSCT¼ haematopoietic stem cell transplantation; IV¼ intravenous; N¼ total number of subjects randomised; NS¼ not specified; OD¼ once daily; Pub¼ publication; PO¼ oral; TID¼ three times daily. Surrogate marker evaluation for invasive fungal infection includes galactomannin and beta-D glucan testing. Table 2 Risk of bias assessment of included articles Adequate Adequate Description of Selective sequence allocation withdrawals Intention to outcome Study author generation concealment Blinding and dropouts treat analysis report Bodey et al, 1994 Yes Unclear No Yes No No Annaloro et al, 1995 Unclear Unclear No No Yes No Huijgens et al, 1999a Unclear Unclear Yes Yes No No Morgenstern et al, 1999b Yes Inadequate No No No Yes Timmers et al, 2000a Unclear Unclear No No No No Wolff et al, 2000a Unclear Unclear No No Yes No Koh et al, 2002b Unclear Unclear No No Yes No Winston et al, 2003 Unclear Yes No Yes No No Marr et al, 2004 Unclear Unclear No Yes No No van Burik et al, 2004 Yes Yes Yes Yes No No Choi et al, 2005 Unclear Unclear No No No No Glasmacher et al, 2006 Yes Yes No Yes No No Oren et al, 2006a Yes Unclear No No No No Cornely et al, 2007 Unclear Unclear No No Yes No Ito et al, 2007a Yes Unclear No Yes No No Ullmann et al, 2007 Unclear Unclear Yes No Yes No Hiramatsu et al, 2008a Unclear Unclear No Yes No No Sawada et al, 2009b Unclear Yes No No No No Ota et al, 2010 Unclear Unclear No No No Wingard et al, 2010 Yes Yes Yes Yes Yes No & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table 3 Synthesised primary and secondary outcomes of mould-active vs fluconazole prophylaxis Outcome Trials (patients) RR (95% CI) P-value Proven or probable IFI 18 (4802) 0.71 (0.52, 0.98) 0.03 Invasive aspergillosis 15 (4503) 0.53 (0.37, 0.75) 0.0004 Adverse events requiring antifungal treatment discontinuation or modification 16 (4493) 1.95 (1.24, 3.07) 0.004 IFI-related mortality 15 (4272) 0.67 (0.47, 0.96) 0.03 Invasive aspergillosis-related mortality 9 (2614) 0.62 (0.23, 1.71) 0.36 Overall mortality 16 (4870) 1.00 (0.88, 1.13) 0.96 Abbreviations: CI¼ confidence interval; IFI¼ invasive fungal infection; RR¼ risk ratio. RRo1 represents an advantage of mould-active coverage using a random-effects model. Mould-active Fluconazole Risk ratio Risk ratio Weight Study or subgroup Events Total Events Total (%) M-H, random, 95% Cl Year M – H, random, 95% Cl Bodey (1994) 10 36 5 41 7.3 2.28 (0.86, 6.04) 1994 Annaloro (1995) 4 31 128 2.0 3.61 (0.43, 30.43) 1995 Huijgens (1999) 4 101 4 101 4.4 1.00 (0.26, 3.89) 1999 Timmers (2000) 0 12 0 12 Not estimable 2000 Koh (2002) 11 86 12 100 9.9 1.07 (0.50, 2.29) 2002 Winston (2003) 6 71 17 67 8.5 0.33 (0.14, 0.79) 2003 Marr (2004) 20 151 25 148 14.0 0.78 (0.46, 1.35) 2004 van Burik (2004) 7 425 11 457 7.7 0.68 (0.27, 1.75) 2004 Choi (2005) 0 40 0 38 Not estimable 2005 Glasmacher (2006) 4 248 5 246 4.7 0.79 (0.22, 2.92) 2006 Oren (2006) 8 96 9 99 8.0 0.92 (0.37, 2.28) 2006 Cornely (2007) 4 239 19 240 6.4 0.21 (0.07, 0.61) 2007 Ulmann (2007) 16 301 27 299 12.8 0.59 (0.32, 1.07) 2007 Ito (2007) 0 103 3 106 1.1 0.15 (0.01, 2.81) 2007 Hiramatsu (2008) 1 50 1 50 1.3 1.00 (0.06, 15.55) 2008 Sawada (2009) 0 54 0 53 Not estimable 2009 Wingard (2010) 14 305 24 295 12.0 0.56 (0.30, 1.07) 2010 Ota (2010) 0 36 0 37 Not estimable 2010 Total (95% Cl) 2385 2417 100.0 0.71 (0.52, 0.98) Total events 109 163 2 2 2 Heterogeneity:  = 0.11;  = 19.53, df = 13 (P =0.11); I = 33% 0.01 0.1 1 10 100 Test for overall effect: Z = 2.11 (P = 0.03) Favours mould-active Favours fluconazole Figure 2 Forest plot of effect of mould-active vs fluconazole prophylaxis on the primary outcome, proven or probable invasive fungal infection. Squares to the left of the vertical line indicate a decreased risk of developing an event in patients receiving mould-active prophylaxis. Horizontal lines through the squares represent 95% CIs. The diamonds represents the overall RR from the meta-analyses and the corresponding 95% CIs. allowed more precise estimation of the effect of mould-active a small proportion of overall mortality within this time frame in prophylaxis on overall mortality. Furthermore, we examined an these populations. The second possibility that may explain the additional clinically important outcome, namely adverse events discrepancy between a reduction in IFD incidence and no effect on resulting in discontinuation of antifungal prophylaxis, which overall mortality may relate to the use of galactomannan tests provides more information to judge the overall utility of mould- (Marr et al, 2005). Mould-active agents are known to reduce the active prophylaxis. sensitivity of this test and thus, it is possible that the reduction in We found that mould-active prophylaxis, when compared with IFD seen with anti-mould agents is actually spurious. The third fluconazole prophylaxis, reduces IFI-related mortality but does not possibility is that mould-active prophylaxis increases non-IFI- influence overall mortality with a point estimate RR of 1.0. The related deaths. This hypothesis is supported by the increase in 95% CI around the overall mortality estimate does not exclude adverse events observed in the mould-active prophylaxis arm. clinically meaningful benefit or harm since the interval was Furthermore, it is possible that drug interactions further 0.88–1.13. As IFI-related mortality is a component of overall contributed to increased patient deaths. mortality, it is interesting to see discordance in these two results. There are at least three downsides of mould-active antifungal There are at least three possibilities to explain this discordance. prophylaxis. First, mould-active prophylaxis may be associated First, the proportion of IFI-related mortality could be such a small with increased adverse events compared with fluconazole prophy- portion of overall mortality that reductions in IFI-related mortality laxis as we have demonstrated. Second, mould-active prophylaxis may not detectably impact on mortality. However, there are two with non-fluconazole azoles may be associated with significant observations that argue against this hypothesis. First, the point drug interactions and the impact of these interactions has not been estimate for overall mortality was 1.0, which suggests no reduction fully evaluated. Third is the issue of costs. Many of the mould- in mortality. Second, mortality was observed for only 3 months active agents are associated with large costs given the duration of and thus, it is hard to envision that IFI-related mortality would be prophylaxis for patients with leukaemia or undergoing allogeneic British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al prophylaxis may be lower (Lehrnbecher et al, 2008). In contrast, Table 4 Stratified analyses by mould-active agent amphotericin B formulations and echinocandins are only available P-value in parenteral formulation and, thus, their administration in a for a prophylactic manner would be expected to have a sizeable impact Trials RR interaction Outcome (patients) (95% CI) P-value test on quality of life. This study has several limitations. First and most importantly, Mould-active agent we combined several different classes of mould-active antifungals Proven or probable IFI 0.1 that are expected to have different efficacy and toxicity profiles. Amphotericin 3 (287) 1.46 (0.70, 3.05) 0.31 Other azoles 12 (3426) 0.60 (0.43, 0.84) 0.003 However, the stratified analysis failed to illustrate important Echinocandin 3 (1089) 0.71 (0.29, 1.73) 0.45 differences in outcome by mould-active antifungal class. Second, fungal classification and reporting was not consistent in the studies Invasive aspergillosis 0.29 Amphotericin 3 (618) 1.18 (0.28, 4.97) 0.82 included although we attempted to address this limitation by Other azoles 9 (2796) 0.52 (0.36, 0.76) 0.0006 re-classifying infections using the EORTC/MSG definitions for IFI Echinocandin 3 (1089) 0.19 (0.03, 1.11) 0.07 (Ascioglu et al, 2002). Third, it is possible that surveillance for IFI IFI-related mortality using galactomannan and beta-D-glucan testing may have altered Amphotericin 4 (642) 0.91 (0.39, 2.16) 0.83 the efficacy of mould-active prophylaxis. There are an insufficient Other azoles 9 (2648) 0.64 (0.38, 1.08) 0.09 number of studies that used such testing to be able to explore this Echinocandin 2 (982) 0.70 (0.12, 4.28) 0.70 effect. Finally, it is also important to mention that only one study IA-related mortality 0.43 included children only, and thus, we are unable to determine if the Amphotericin 2 (101) 3.41 (0.14, 81.07) 0.45 effect of mould-active prophylaxis compared with fluconazole Other azoles 5 (1531) 0.63 (0.18, 2.13) 0.46 Echinocandin 2 (982) 0.27 (0.03, 2.38) 0.24 differs between children and adults. This deficiency supports the need for future randomised trials in children in order determine Overall mortality 0.79 the effect of mould-active prophylaxis in paediatrics. Amphotericin 3 (618) 1.11 (0.78, 1.59) 0.55 Other azoles 11 (3270) 0.99 (0.86, 1.14) 0.89 Future studies should attempt to better describe the potential Echinocandin 2 (982) 0.89 (0.42, 1.88) 0.76 benefits and downsides of mould-active prophylaxis. This may be accomplished through future randomised trials of agents thought AEs requiring antifungal 0.001 treatment discontinuation to be less toxic and through individual patient-level meta-analyses. or modification Furthermore, patient preferences and costs deserve future Amphotericin 4 (642) 5.98 (1.20, 29.86) 0.03 exploration. Mould-active antifungal prophylaxis may have a large Other azoles 10 (2869) 1.92 (1.19, 3.08) 0.007 Echinocandin 2 (982) 0.59 (0.34, 1.03) 0.06 economic impact on care of patients with haematological malignancy and undergoing HSCT; we must be relatively certain Abbreviations: AEs¼ adverse events; CI¼ confidence interval; IA¼ invasive asper- a of benefits before routine implementation. gillosis; IFI¼ invasive fungal infection; RR¼ risk ratio. RRo1 represents an advantage In conclusion, this meta-analysis demonstrates that prophylaxis of mould-active coverage compared with fluconazole using a random-effects model. with mould-active compared with fluconazole prophylaxis significantly reduces the number of proven or probable IFI, IA, and IFI-related mortality in patients receiving chemotherapy or HSCT. Cost-effectiveness analyses have shown that posaconazole is undergoing HSCT. However, mould-active antifungal prophylaxis a cost-effective strategy for preventing IFI, compared with also increases adverse events leading to antifungal modification or fluconazole, in patients with GVHD and with acute myeloid discontinuation and does not impact on overall mortality. Future leukaemia/myelodysplastic syndrome (Stam et al, 2008; de la work to better understand the benefits and downsides of individual Camara et al, 2010; Dranitsaris and Khoury, 2011). In adult classes of mould-active antifungals and to explore patient patients undergoing HSCT, micafungin has been shown to reduce preferences and costs is warranted. hospital costs and total patient costs (Schonfeld et al, 2008) and to be cost effective (Sohn et al, 2009), compared with fluconazole. However, these analyses have been based upon single studies rather than synthesised results. Further exploration of costs that ACKNOWLEDGEMENTS take into consideration patient preferences are warranted. Finally, there has been little evaluation of patient preferences for antifungal We would like to thank Ryoko Ingram who generously assisted prophylaxis. Agents such as posaconazole, voriconazole and with the translation of the article by Sawada into English, as well as itraconazole have an oral formulation and thus, may have a lesser Elizabeth Uleryk who provided invaluable feedback for the impact on quality of life given that administration may occur systematic literature search. LS is supported by a New Investigator on an outpatient basis. However, compliance of oral antifungal Award with the Canadian Institutes of Health Research. REFERENCES Annaloro C, Oriana A, Tagliaferri E, Bertolli V, Della Volpe A, Soligo D, Bodey GP, Anaissie EJ, Elting LS, Estey E, O’Brien S, Kantarjian H (1994) Ibatici A, Pozzoli E, Lambertenghi Deliliers GL (1995) Efficacy of Antifungal prophylaxis during remission induction therapy for acute different prophylactic antifungal regimens in bone marrow transplanta- leukemia fluconazole versus intravenous amphotericin B. Cancer 73(8): tion. Haematologica 80(6): 512–517 2099–2106 Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Choi SM, Lee DG, Choi JH, Park SH, Eom KS (2005) Itraconazole oral Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, solution versus fluconazole syrup for prevention of invasive fungal Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh infections in patients receiving hematopoietic stem cell transplantation: TJ. Invasive Fungal Infections Cooperative Group of the European prospective, randomized, comparative clinical trial. Infect Chemother Organization for R, Treatment of CMycoses Study Group of the National 37(2): 71–78 Institute of A, Infectious D (2002) Defining opportunistic invasive fungal Cornely OA, Bohme A, Buchheidt D, Einsele H, Heinz WJ, Karthaus M, infections in immunocompromised patients with cancer and hemato- Krause SW, Kruger W, Maschmeyer G, Penack O, Ritter J, Ruhnke M, poietic stem cell transplants: an international consensus. Clin Infect Sandherr M, Sieniawski M, Vehreschild JJ, Wolf HH, Ullmann AJ. Diseas 34(1): 7–14 Recommendations of the Infectious Diseases Working Party of the & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al German Society for Haematology and Oncology (2009) Primary Huijgens PC, Simoons-Smit AM, van Loenen AC, Prooy E, van Tinteren H, prophylaxis of invasive fungal infections in patients with hematologic Ossenkoppele GJ, Jonkhoff AR (1999b) Fluconazole versus malignancies. Haematologica 94(1): 113–122 itraconazole for the prevention of fungal infections in haemato-oncology. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, J Clin Pathol 52(5): 376–380 Helfgott D, Holowiecki J, Stockelberg D, Goh Y-T, Petrini M, Hardalo C, Ito Y, Ohyashiki K, Yoshida I, Takeuchi M, Aoyama Y, Mugitani A, Suresh R, Angulo-Gonzalez D (2007) Posaconazole vs fluconazole or Matsuura Y, Wakita H, Matsuda M, Sakamoto E, Kiguchi T, Urabe A, itraconazole prophylaxis in patients with neutropenia. N Engl J Med Tamura K, Kanamaru A, Masaoka T (2007a) The prophylactic effect of 356(4): 348–359 itraconazole capsules and fluconazole capsules for systemic fungal de la Camara R, Jarque I, Sanz MA, Grau S, Casado MA, Sabater FJ, infections in patients with acute myeloid leukemia and myelodysplastic Carreras E (2010) Economic evaluation of posaconazole vs fluconazole in syndromes: a Japanese multicenter randomized, controlled study the prevention of invasive fungal infections in patients with GVHD Int J Hematol 85(2): 121–127 following haematopoietic SCT. Bone Marrow Transplant 45(5): 925–932 Ito Y, Ohyashiki K, Yoshida I, Takeuchi M, Aoyama Y, Mugitani A, De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Matsuura Y, Wakita H, Matsuda M, Sakamoto E, Kiguchi T, Urabe A, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Tamura K, Kanamaru A, Masaoka T (2007b) The prophylactic effect of Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R itraconazole capsules and fluconazole capsules for systemic fungal Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Munoz P, Odds FC, infections in patients with acute myeloid leukemia and myelodysplastic Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli syndromes: a Japanese multicenter randomized, controlled study C, Wingard JR, Zaoutis T, Bennett JE. European Organization for R, Int J Hematol 85(2): 121–127 Treatment of Cancer/Invasive Fungal Infections Cooperative GNational Koh LP, Kurup A, Goh YT, Fook-Chong SMC, Tan PHC (2002a) Institute of AInfectious Diseases Mycoses Study Group Consensus G Randomized trial of fluconazole versus low-dose amphotericin B in (2008) Revised definitions of invasive fungal disease from the European prophylaxis against fungal infections in patients undergoing hemato- Organization for Research and Treatment of Cancer/Invasive Fungal poietic stem cell transplantation. Am J Hematol 71(4): 260–267 Infections Cooperative Group and the National Institute of Allergy and Koh LP, Kurup A, Goh YT, Fook-Chong SMC, Tan PHC (2002b) Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Randomized trial of fluconazole versus low-dose amphotericin B in Group. Clin Infect Dis 46(12): 1813–1821 prophylaxis against fungal infections in patients undergoing hemato- Dranitsaris G, Khoury H (2011) Posaconazole versus fluconazole or poietic stem cell transplantation. J Clin Pathol 71(4): 260–267 itraconazole for prevention of invasive fungal infections in patients Lehrnbecher T, Ethier MC, Zaoutis T, Creutzig U, Gamis A, Reinhardt D, undergoing intensive cytotoxic therapy for acute myeloid leukemia or Aplenc R, Sung L (2009) International variations in infection supportive myelodysplasia: a cost effectiveness analysis. Support Care Cancer 19(11): care practices for paediatric patients with acute myeloid leukaemia 1807–1813 Br J Haematol 147(1): 125–128 Ethier MC (2011) Fluconazole Compared to Anti-Mold Coverage for Lehrnbecher T, Laws HJ, Boehm A, Dworzak M, Janssen G, Simon A, Groll Antifungal Prophylaxis to Prevent Invasive Fungal Infections in Cancer AH (2008) Compliance with anti-infective preventive measures: a Patients receiving Chemotherapy or after Hematopoietic Stem-Cell multicentre survey among paediatric oncology patients. Eur J Cancer Transplantation: A Systematic Review and Meta-Analysis of Randomized 44(13): 1861–1865 Controlled Trials PROSPERO: International prospective register of Maertens J, Marchetti O, Herbrecht R, Cornely OA, Fluckiger U, Frere P, systematic reviewsCRD420111174. http://www.crd.york.ac.uk/prospero/) Gachot B, Heinz WJ, Lass-Florl C, Ribaud P, Thiebaut A, Cordonnier C. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad, Third European Conference on Infections in L (2011) European Rolston KV, Young JA, Wingard JR (2011) Clinical practice guideline for guidelines for antifungal management in leukemia and hematopoietic the use of antimicrobial agents in neutropenic patients with cancer: 2010 stem cell transplant recipients: summary of the ECIL 3—2009 update. update by the Infectious Diseases Society of America. Clin Infect Dis Bone Marrow Transplant 46(5): 709–718 52(4): 427–431 Mahfouz T, Anaissie E (2003) Prevention of fungal infections Glasmacher A, Cornely O, Ullmann AJ, Wedding U, Bodenstein H, Wandt in the immunocompromised host. Curr Opin Investig Drugs 4(8): H, Boewer C, Pasold R, Wolf H-H, Hanel M, Dolken G, Junghanss C, 974–990 Andreesen R, Bertz H. Itraconazole Research Group of G (2006) An Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA open-label randomized trial comparing itraconazole oral solution with Nichols WG, Musher B, Corey L (2004) Itraconazole versus fluconazole fluconazole oral solution for primary prophylaxis of fungal infections in for prevention of fungal infections in patients receiving allogeneic stem patients with haematological malignancy and profound neutropenia cell transplants. Blood 103(4): 1527–1533 J Antimicrob Chemother 57(2): 317–325 Marr KA, Laverdiere M, Gugel A, Leisenring W (2005) Antifungal therapy Glasmacher A, Prentice A, Gorschluter M, Engelhart S, Hahn C, Djulbegovic decreases sensitivity of the Aspergillus galactomannan enzyme immu- B, Schmidt-Wolf IG (2003) Itraconazole prevents invasive fungal infections noassay. Clin Infect Dis 40(12): 1762–1769 in neutropenic patients treated for hematologic malignancies: evidence Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred from a meta-analysis of 3597 patients. J Clin Oncol 21(24): 4615–4626 reporting items for systematic reviews and meta-analyses: the PRISMA Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B statement. Ann Int Med 151(4): 264–269 Kaizer H, Shadduck RK, Shea TC, Stiff P, Friedman DJ (1992) A Morgenstern GR, Prentice AG, Prentice HG, Ropner JE, Schey SA, Warnock controlled trial of fluconazole to prevent fungal infections in patients DW. U.K. Multicentre Antifungal Prophylaxis Study Group (1999a) A undergoing bone marrow transplantation. N Engl J Med 326(13): 845–851 randomized controlled trial of itraconazole versus fluconazole for the Higgins J, Green S (2009) Cochrane Handbook for Systematic Reviews of prevention of fungal infections in patients with haematological Interventions Version 5.0.2 (updated September 2009). The Cochrane malignancies. Br J Haematol 105(4): 901–911 Collaboration 34(18): 1929–1941 Morgenstern GR, Prentice AG, Prentice HG, Ropner JE, Schey SA, Warnock Hiramatsu Y, Maeda Y, Fujii N, Saito T, Nawa Y, Hara M, Yano T, Asakura DW. U.K. Multicentre Antifungal Prophylaxis Study Group (1999b) A S, Sunami K, Tabayashi T, Miyata A, Matsuoka K-i, Shinagawa K, Ikeda randomized controlled trial of itraconazole versus fluconazole for the K, Matsuo K, Tanimoto M, West-Japan H, Oncology G (2008a) Use of prevention of fungal infections in patients with haematological micafungin versus fluconazole for antifungal prophylaxis in neutropenic malignancies. Br J Haematol 105(4): 901–911 patients receiving hematopoietic stem cell transplantation. Int J Hematol Oren I, Rowe JM, Sprecher H, Tamir A, Benyamini N, Akria L, Gorelik A, 88(5): 588–595 Dally N, Zuckerman T, Haddad N, Fineman R, Dann EJ (2006a) A Hiramatsu Y, Maeda Y, Fujii N, Saito T, Nawa Y, Hara M, Yano T prospective randomized trial of itraconazole vs fluconazole for the Asakura S, Sunami K, Tabayashi T, Miyata A, Matsuoka K-i, Shinagawa prevention of fungal infections in patients with acute leukemia and K, Ikeda K, Matsuo K, Tanimoto M, West-Japan H, Oncology G (2008b) hematopoietic stem cell transplant recipients. Bone Marrow Transplant Use of micafungin versus fluconazole for antifungal prophylaxis in 38(2): 127–134 neutropenic patients receiving hematopoietic stem cell transplantation. Oren I, Rowe JM, Sprecher H, Tamir A, Benyamini N, Akria L, Gorelik A, Int J Hematol 88(5): 588–595 Dally N, Zuckerman T, Haddad N, Fineman R, Dann EJ (2006b) A Huijgens PC, Simoons-Smit AM, van Loenen AC, Prooy E, van Tinteren H, prospective randomized trial of itraconazole vs fluconazole for the Ossenkoppele GJ, Jonkhoff AR (1999a) Fluconazole versus itraconazole prevention of fungal infections in patients with acute leukemia and for the prevention of fungal infections in haemato-oncology. J Clin hematopoietic stem cell transplant recipients. Bone Marrow Transplant Pathol 52(5): 376–380 38(2): 127–134 British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Ota S, Matsukawa T, Kosugi M, Shima K, Katsura Y, Kanaya M, Matsuoka prophylaxis in high risk neutropenic patients in the Netherlands. Eur J S, Noguchi S, Fujii S, Nakata M, Imai K, Hirano T, Kobayashi N, Haematol 81(6): 467–474 Ogasawara M, Kiyama Y, Kasai M (2010) Itraconazole versus fluconazole Sutton AJ, Duval SJ, Tweedie RL, Abrams KR, Jones DR (2000) Empirical for prophylaxis against invasive fungal infections during neutropenia in assessment of effect of publication bias on meta-analyses. BMJ 320(7249): patients receiving haematopoietic stem cell transplants. Bone Marrow 1574–1577 Transplant. Conference: 36th Annual Meeting of the European Group for Timmers GJ, Zweegman S, Simoons-Smit AM, van Loenen AC, Touw D, Blood and Marrow Transplantation, EBMT 2010 Vienna Austria. Huijgens PC (2000a) Amphotericin B colloidal dispersion (Amphocil) vs Conference Start: 20100321 Conference End: 20100324. Conference fluconazole for the prevention of fungal infections in neutropenic Publication: (var.pagings) 45: S394 patients: data of a prematurely stopped clinical trial. Bone Marrow Pagano L, Caira M, Candoni A, Offidani M, Martino B, Specchia G, Transplant 25(8): 879–884 Pastore D, Stanzani M, Cattaneo C, Fanci R, Caramatti C, Rossini F, Timmers GJ, Zweegman S, Simoons-Smit AM, van Loenen AC, Touw D, Luppi M, Potenza L, Ferrara F, Mitra ME, Fadda RM, Invernizzi R, Aloisi Huijgens PC (2000b) Amphotericin B colloidal dispersion (Amphocil) vs T, Picardi M, Bonini A, Vacca A, Chierichini A, Melillo L, de Waure C, fluconazole for the prevention of fungal infections in neutropenic Fianchi L, Riva M, Leone G, Aversa F, Nosari A (2010) Invasive patients: data of a prematurely stopped clinical trial. Bone Marrow aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 Transplantation 25(8): 879–884 registry study. Haematologica 95(4): 644–650 Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo Prentice AG, Glasmacher A, Djulbegovic B (2006) In meta-analysis SR, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, itraconazole is superior to fluconazole for prophylaxis of systemic Patino H, Durrant S (2007) Posaconazole or fluconazole for prophylaxis fungal infection in the treatment of haematological malignancy. Br J in severe graft-versus-host disease. [Erratum appears in N Engl J Med. Haematol 132(5): 656–658 2007 Jul 26;357(4):428] N Engl J Med 356(4): 335–347 Robenshtok E, Gafter-Gvili A, Goldberg E, Weinberger M, Yeshurun M, van Burik J-AH, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Leibovici L, Paul M (2007) Antifungal prophylaxis in cancer patients Vesole DH, Bunin N, Wall DA, Hiemenz JW, Satoi Y, Lee JM, Walsh TJ. after chemotherapy or hematopoietic stem-cell transplantation: systema- National Institute of AInfectious Diseases Mycoses Study G (2004) tic review and meta-analysis. J Clin Oncol 25(34): 5471–5489 Micafungin versus fluconazole for prophylaxis against invasive fungal Rotstein C, Bow EJ, Laverdiere M, Ioannou S, Carr D, Moghaddam N. The infections during neutropenia in patients undergoing hematopoietic Canadian Fluconazole Prophylaxis Study Group (1999) Randomized stem cell transplantation. Clin Infect Dis 39(10): 1407–1416 placebo-controlled trial of fluconazole prophylaxis for neutropenic Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr cancer patients: benefit based on purpose and intensity of cytotoxic KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik JA, therapy. Clin Infect Dis 28(2): 331–340 Wingard JR, Patterson TF. Infectious Diseases Society of A (2008) Sawada A, Sakata N, Higuchi B, Takeshita Y, Ishihara T, Sakata A, Kouroki Treatment of aspergillosis: clinical practice guidelines of the Infectious M, Kondo O, Koyama M, Hirano S, Yasui M, Inoue M, Yoshioka A, Kawa Diseases Society of America. Clin Infect Dis 46(3): 327–360 K (2009a) Comparison of micafungin and fosfluconazole as prophylaxis Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten for invasive fungal infection during neutropenia in children undergoing ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, chemotherapy and hematopoietic stem cell transplantation. Rinsho Bolanos-Meade J, Brown J, Dipersio JF, Boeckh M, Marr KA. Blood, Ketsueki—Japanese J Clin Hematol 50(12): 1692–1699 Marrow Transplant Clinical Trials N (2010) Randomized, double-blind Sawada A, Sakata N, Higuchi B, Takeshita Y, Ishihara T, Sakata A, Kouroki trial of fluconazole versus voriconazole for prevention of invasive fungal M, Kondo O, Koyama M, Hirano S, Yasui M, Inoue M, Yoshioka A, Kawa infection after allogeneic hematopoietic cell transplantation. Blood K (2009b) Comparison of micafungin and fosfluconazole as prophylaxis 116(24): 5111–5118 for invasive fungal infection during neutropenia in children undergoing Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, chemotherapy and hematopoietic stem cell transplantation. Rinsho Blumer JL, Leitz GJ, Territo MC (2003) Intravenous and oral itraconazole Ketsueki 50(12): 1692–1699 versus intravenous and oral fluconazole for long-term antifungal Schonfeld W, Wang Cheng J, Tong KB, Seifeldin R (2008) Cost-effectiveness prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. analysis of antifungal prophylaxis in patients undergoing hematopoietic A multicenter, randomized trial. Ann Int Med 138(9): 705–713 stem cell transplantation. Clin Ther 30(5): 964–973 Wolff SN, Fay J, Stevens D, Herzig RH, Pohlman B, Bolwell B, Lynch J, Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR, Ericson S, Freytes CO, LeMaistre F, Collins R, Pineiro L, Greer J, Stein R, Meyers JD, Bowden RA (1995) Efficacy and safety of fluconazole Goodman SA, Dummer S (2000a) Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone prophylaxis for fungal infections after marrow transplantation— a prospective, randomized, double-blind study. J Infect Dis 171(6): marrow transplantation: a study of the North American Marrow 1545–1552 Transplant Group. Bone Marrow Transplant 25(8): 853–859 Sohn HS, Lee TJ, Kim J, Kim D (2009) Cost-effectiveness analysis of Wolff SN, Fay J, Stevens D, Herzig RH, Pohlman B, Bolwell B, Lynch J, micafungin versus fluconazole for prophylaxis of invasive fungal Ericson S, Freytes CO, LeMaistre F, Collins R, Pineiro L, Greer J, Stein R, infections in patients undergoing hematopoietic stem cell transplanta- Goodman SA, Dummer S (2000b) Fluconazole vs low-dose amphotericin tion in Korea. Clin Ther 31(5): 1105–1115, discussion 1066-1068 B for the prevention of fungal infections in patients undergoing bone Stam WB, O’Sullivan AK, Rijnders B, Lugtenburg E, Span LF, Janssen JJ, marrow transplantation: a study of the North American Marrow Jansen JP (2008) Economic evaluation of posaconazole vs standard azole Transplant Group. Bone Marrow Transplant 25(8): 853–859 & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al APPENDIX Table A1 Search strategies used to identify randomised study of mould-active vs fluconazole antifungal prophylaxis in patients with cancer or undergoing haematopoietic stem cell transplantation # Searches Results Ovid MEDLINE(R) 1948 to August (week 2) 2011 (run on August 24, 2011) 1 Fluconazole/ or (fluconazol* or flucolich or arnazole or beagyne or elazor or flucobeta or solacap or diflucan or triflucan or 13 405 ‘uk 49858’ or uk49858 or neofomiral or lavisa or zonal or ‘fluc hexal’ or fluchexal or oxifungol or fungata or loitin or flunazul or zoltrix).mp. 2 exp Aspergillus/pc or (exp Aspergillus/ and (prophyla* or prevent*).mp.) or exp Mycoses/pc or (exp Mycoses/ and (prophyla* or prevent*).mp.) or 64 991 (prophylaxis or (prevent* adj2 (fungal or fungus))).ti,ab. 3 Stem Cell Transplantation.mp. or exp Stem Cell Transplantation/ 45 185 4 exp neoplasms/ or (cancer or oncolog*).mp. 2 389 250 5 exp Neutropenia/ or neutropeni*.mp. 28 301 63or4or5 2 426 526 7 1 and 2 and 6 473 8 randomised controlled trial.pt. 314 177 9 controlled clinical trial.pt. 83 186 10 randomised.ab. 220 043 11 drug therapy.fs. 1 486 777 12 randomly.ab. 158 898 13 trial.ab. 227 567 14 groups.ab. 1 054 838 15 8 or 9 or 10 or 11 or 12 or 13 or 14 2 740 074 16 exp animals/ not humans.sh. 3 651 958 17 15 not 16 2 325 347 18 7 and 17 343 Database: EMBASE o1980 to 2011 Week 334 (run on 24 August 2011) 1 fluconazole/ or (fluconazol* or flucolich or arnazole or beagyne or elazor or flucobeta or solacap or diflucan or triflucan or ‘uk 49858’ or uk49858 or 29 035 neofomiral or lavisa or zonal or ‘fluc hexal’ or fluchexal or oxifungol or fungata or loitin or flunazul or zoltrix or Afungil or Alflucoz or Baten or Biocanol or Biozolene or CCRIS 7211 or Canzol or Cryptal or DRG-0005 or Dimycon or Elazor or Mutum or Pritenzol or Syscan or Triconal or Zemyc or Zoltec).mp. 2 (exp Aspergillus/ and (prevent* or prophyla*)).mp. or exp mycosis/pc or (exp mycosis/ and (prevent* or prophyla*)).mp. or ((exp Aspergillus/ or 16 911 exp mycosis/) and (prophylaxis/ or infection prevention/)) 3 stem cell transplantation.mp. or exp stem cell transplantation/ 59 342 4 exp neoplasms/ or (cancer or oncolog*).mp. 2 848 209 5 exp NEUTROPENIA/ or exp FEBRILE NEUTROPENIA/ or neutropenia.mp. 61 135 6 3 or 4 2 876 781 7 1 and 2 and 6 1655 8 randomised controlled trial/ or ct.fs. or random$.mp. or doubl$adj blind$.mp. 996 967 9 7 and 8 554 EBM Reviews—Cochrane Central Register of Controlled Trials, 3rd Quarter 2011 (run on 24 August 2011) 1 fluconazole/ or (fluconazol* or flucolich or arnazole or beagyne or elazor or flucobeta or solacap or diflucan or triflucan or ‘uk 49858’ or uk49858 or 668 neofomiral or lavisa or zonal or ‘fluc hexal’ or fluchexal or oxifungol or fungata or loitin or flunazul or zoltrix or Afungil or Alflucoz or Baten or Biocanol or Biozolene or CCRIS 7211 or Canzol or Cryptal or DRG-0005 or Dimycon or Elazor or Mutum or Pritenzol or Syscan or Triconal or Zemyc or Zoltec).mp. 2 exp Aspergillus/pc or (exp Aspergillus/ and (prophyla* or prevent*).mp.) or exp Mycoses/pc or (exp Mycoses/ and (prophyla* or prevent*).mp.) or 10 404 (prophylaxis or (prevent* adj2 (fungal or fungus))).ti,ab. 3 Stem Cell Transplantation.mp. or exp Stem Cell Transplantation/ or exp Bone Marrow Transplantation/ 2679 4 exp neoplasms/ or (cancer or oncolog*).mp. 56 297 5 neutropenia.mp. or exp Neutropenia/ 3010 63or4or5 58 299 7 1 and 2 and 6 104 Table A2 Stratified analyses by blinding and intention to treat analysis Outcome Trials (patients) RR* (95% CI) P-value P-value for interaction test Blinding Proven or probable IFI 0.52 Blinded 4 (2284) 0.62 (0.42, 0.91) 0.01 Not blinded 14 (2518) 0.71 (0.52, 0.98) 0.27 Invasive aspergillosis 0.60 Blinded 4 (2284) 0.47 (0.23, 0.98) 0.04 Not blinded 11 (22196) 0.59 (0.37, 0.95) 0.03 British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table A2 (Continued ) Outcome Trials (patients) RR* (95% CI) P-value P-value for interaction test IFI-related mortality 0.88 Blinded 3 (1686) 0.68 (0.19, 2.40) 0.54 Not blinded 12 (2586) 0.75 (0.49, 1.15) 0.19 IA-related mortality 0.60 Blinded 2 (1084) 0.84 (0.15, 4.91) 0.85 Not blinded 7 (1530) 0.46 (0.12, 1.77) 0.26 Overall mortality 0.23 Blinded 4 (2284) 0.92 (0.76, 1.11) 0.36 Not blinded 12 (2586) 1.07 (0.90, 1.28) 0.44 ITT analysis Proven or probable IFI 0.83 ITT 4 (1445) 0.74 (0.46, 1.17) 0.2 No ITT 14 (3357) 0.69 (0.44, 1.07) 0.1 Invasive aspergillosis 0.55 ITT 5 (1800) 0.47 (0.27, 0.80) 0.006 No ITT 10 (2703) 0.58 (0.37, 0.91) 0.02 IFI-related mortality 0.60 ITT 5 (1280) 0.60 (0.27, 1.33) 0.21 No ITT 10 (2992) 0.77 (0.49, 1.22) 0.27 IA-related mortality NA ITT 1 (59) Not estimable NA No ITT 8 (2555) 0.62 (0.23, 1.71) 0.36 Overall mortality NA ITT 0 (0) Not estimable NA No ITT 16 (4870) 1.00 (0.88, 1.13) 0.96 Abbreviations: CI¼ confidence interval; IA¼ invasive aspergillosis; IFI¼ invasive fungal infection; ITT¼ intention-to-treat; NA¼ not applicable; RR¼ relative risk. *RRo1 represents an advantage of mould-active coverage compared with fluconazole using a random-effects model. Table A3 Stratified analyses by study population and fluconazole dose Outcome Trials (patients) RR* (95% CI) P-value P-value for interaction test Study population Proven or probable IFI 0.82 HSCT 9 (2415) 0.70 (0.49, 0.99) 0.004 Chemotherapy 4 (1259) 0.59 (0.15, 2.27) 0.45 Invasive aspergillosis 0.73 HSCT 8 (2619) 0.47 (0.29, 0.75) 0.002 Chemotherapy 3 (780) 0.60 (0.16, 2.28) 0.45 IFI-related mortality 0.96 HSCT 8 (2097) 0.81 (0.50, 1.31) 0.39 Chemotherapy 2 (571) 0.78 (0.17, 3.46) 0.74 IA-related mortality 0.23 HSCT 4 (1065) 0.27 (0.03, 2.38) 0.24 Chemotherapy 2 (571) 1.69 (0.21, 13.59) 0.62 Overall Mortality 0.42 HSCT 9 (2697) 1.06 (0.90, 1.25) 0.50 Chemotherapy 2 (571) 0.86 (0.54, 1.38) 0.54 AEs requiring antifungal treatment discontinuation or modification 0.43 HSCT 8 (2111) 2.14 (0.94, 4.87) 0.07 Chemotherapy 3 (780) 1.51 (1.16, 1.98) 0.0003 Fluconazole dose Proven or probable IFI 0.18 Fluconazole X400 mg per day 12 (4044) 0.65 (0.46, 0.93) 0.02 Fluconazole o400 mg per day 6 (758) 1.07 (0.57, 2.00) 0.84 Invasive aspergillosis 0.11 Fluconazole X400 mg per day 11 (3847) 0.49 (0.34, 0.70) 0.0001 Fluconazole o400 mg per day 4 (656) 1.42 (0.41, 4.93) 0.59 IFI-related mortality 0.14 Fluconazole X400 mg per day 9 (3142) 0.57 (0.38, 0.86) 0.007 Fluconazole o400 mg per day 6 (1130) 1.22 (0.49, 3.02) 0.67 IA-related mortality 0.87 Fluconazole X400 mg per day 5 (1748) 0.51 (0.13, 1.95) 0.32 Fluconazole o400 mg per day 4 (866) 0.63 (0.07, 6.09) 0.69 & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table A3 (Continued ) Outcome Trials (patients) RR* (95% CI) P-value P-value for interaction test Overall mortality 0.87 Fluconazole X400 mg per day 10 (3740) 0.98 (0.85, 1.12) 0.76 Fluconazole o400 mg per day 6 (1130) 1.03 (0.57, 1.88) 0.92 AEs requiring antifungal treatment discontinuation or modification 0.03 Fluconazole X400 mg per day 10 (3213) 1.49 (0.91, 2.43) 0.12 Fluconazole o400 mg per day 6 (1280) 3.19 (2.01, 5.05) 0.0001 Abbreviations: AEs¼ adverse events; CI¼ confidence interval; HSCT¼ haematopoietic stem cell transplantation; IA¼ invasive aspergillosis; IFI¼ invasive fungal infection; ITT¼ intention-to-treat; RR¼ relative risk. *RRo1 represents an advantage of mould-active coverage compared with fluconazole using a random-effects model. Table A4 Meta-regression for primary and secondary outcomes of mould-active vs fluconazole prophylaxis Outcome b s.e. P-value Proven or probable IFI HSCT  0.07 0.35 0.831 Amphotericin 0.86 0.36 0.017 Echinocandin 0.19 0.48 0.698 Other azoles REF REF Fluconazole X400 mg per day  0.52 0.40 0.190 Blinding  0.22 0.26 0.403 ITT  0.24 0.25 0.350 Invasive aspergillosis HSCT  0.35 0.38 0.363 Amphotericin 0.91 0.76 0.233 Echinocandin  0.90 0.91 0.326 Other azoles REF REF Fluconazole X400 mg per day  1.12 0.64 0.080 Blinding  0.10 0.36 0.780 ITT  0.38 0.36 0.286 Adverse events requiring antifungal treatment discontinuation or modification HSCT  0.29 0.52 0.584 Amphotericin 1.06 0.67 0.112 Echinocandin  1.09 0.68 0.112 Other azoles REF REF Fluconazole X400 mg per day  0.83 0.48 0.086 Blinding  1.12 0.30 0.0002 ITT  0.13 0.59 0.833 IFI-related mortality HSCT  0.10 0.48 0.831 Amphotericin 0.37 0.54 0.495 Echinocandin 0.13 0.98 0.896 Other azoles REF REF Fluconazole X400 mg per day  0.70 0.46 0.129 Blinding  0.34 0.41 0.404 ITT  0.42 0.39 0.282 Invasive aspergillosis-related mortality HSCT  0.77 1.35 0.569 Amphotericin 1.17 1.40 0.403 Echinocandin  1.10 1.66 0.506 Other azoles REF REF Fluconazole X400 mg per day  0.50 0.97 0.605 Blinding 0.54 1.00 0.590 ITT 0.35 2.06 0.866 Overall mortality HSCT 0.10 0.20 0.619 Amphotericin 0.14 0.22 0.510 Echinocandin  0.16 0.30 0.591 Other azoles REF REF Fluconazole X400 mg per day  0.17 0.24 0.47 Blinding  0.14 0.15 0.341 ITT  0.05 0.15 0.754 Abbreviations: HSCT¼ haematopoietic stem cell transplantation; IFI¼ invasive fungal infection; ITT¼ intention-to-treat; REF¼ reference category; s.e.¼ standard error. British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table A5 Sensitivity analyses for primary and secondary outcomes of mould-active vs fluconazole prophylaxis Sensitivity analysis-studies of itraconazole Analyses for all capsules removed (Annaloro et al, 1995; included studies Huijgens et al, 1999b) Outcome Risk ratio* (95% CI) P-value Risk ratio* (95% CI) P-value Proven or probable IFI 0.71 (0.52, 0.98) 0.03 0.68 (0.49, 0.94) 0.02 Invasive aspergillosis 0.53 (0.37, 0.75) 0.0004 0.50 (0.35, 0.71) 0.0001 Adverse events requiring antifungal treatment discontinuation 1.95 (1.24, 3.07) 0.004 1.95 (1.24, 3.07) 0.004 or modification IFI-related mortality 0.67 (0.47, 0.96) 0.03 0.62 (0.43, 0.90) 0.01 Invasive aspergillosis-related mortality 0.62 (0.23, 1.71) 0.36 0.41 (0.12, 1.39) 0.15 Overall mortality 1.00 (0.88, 1.13) 0.96 0.99 (0.87, 1.13) 0.85 Sensitivity analysis-studies of Itraconazole 200 mg per day removed (Choi et al, 2005; Ito et al, 2007b; Ota et al, 2010) Proven or probable IFI 0.71 (0.52, 0.98) 0.03 0.72 (0.53, 0.99) 0.05 Invasive aspergillosis 0.53 (0.37, 0.75) 0.0004 0.54 (0.38, 0.76) 0.0005 Adverse events requiring antifungal treatment discontinuation 1.95 (1.24, 3.07) 0.004 1.85 (1.13, 3.03) 0.01 or modification IFI-related mortality 0.67 (0.47, 0.96) 0.03 0.66 (0.46, 0.95) 0.02 Invasive aspergillosis-related mortality 0.62 (0.23, 1.71) 0.36 0.62 (0.23, 1.71) 0.36 Overall mortality 1.00 (0.88, 1.13) 0.96 1.00 (0.88, 1.14) 0.98 Abbreviations: CI¼ confidence interval; IFI¼ invasive fungal infection. *RRo1 represents an advantage of mould-active coverage compared with fluconazole using a random- effects model. This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials

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References (102)

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Springer Journals
Copyright
Copyright © 2012 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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1532-1827
DOI
10.1038/bjc.2012.147
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Abstract

Clinical Studies British Journal of Cancer (2012) 106, 1626–1637 & 2012 Cancer Research UK All rights reserved 0007 – 0920/12 www.bjcancer.com Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials 1,2 2,3 1,4 4,5 6 ,1,7 MC Ethier , M Science , J Beyene , M Briel , T Lehrnbecher and L Sung 1 2 Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto M5G 1X8, Ontario, Canada; Program in Health Research Methodology, McMaster University, Hamilton L8S 4L8, Ontario, Canada; Division of Infectious Diseases, The Hospital for Sick Children, Toronto M5G 1X8, Ontario, Canada; Population Genomics Program, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton L8S 4L8, 5 6 Ontario, Canada; Basel Institute for Clinical Epidemiology and Biostatistics, Basel, Switzerland; Pediatric Hematology and Oncology, University of Frankfurt, Frankfurt, Germany; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto M5G 1X8, Ontario, Canada BACKGROUND: Objectives were to compare systemic mould-active vs fluconazole prophylaxis in cancer patients receiving chemotherapy or haematopoietic stem cell transplantation (HSCT). METHODS: We searched OVID MEDLINE and the Cochrane Central Register of Controlled Trials (1948-August 2011) and EMBASE (1980-August 2011). Randomised controlled trials of mould-active vs fluconazole prophylaxis in cancer or HSCT patients were included. Primary outcome was proven/probable invasive fungal infections (IFI). Analysis was completed by computing relative risks (RRs) using a random-effects model and Mantel–Haenszel method. RESULTS: From 984 reviewed articles, 20 were included in this review. Mould-active compared with fluconazole prophylaxis significantly reduced the number of proven/probable IFI (RR 0.71, 95% CI 0.52 to 0.98; P¼ 0.03). Mould-active prophylaxis also decreased the risk of invasive aspergillosis (IA; RR 0.53, 95% confidence interval (CI) 0.37–0.75; P¼ 0.0004) and IFI-related mortality (RR 0.67, 95% CI 0.47–0.96; P¼ 0.03) but is also associated with an increased risk of adverse events (AEs) leading to antifungal discontinuation (RR 1.95, 95% CI 1.24–3.07; P¼ 0.004). There was no decrease in overall mortality (RR 1.0; 95% CI 0.88–1.13; P¼ 0.96). CONCLUSION: Mould-active compared with fluconazole prophylaxis significantly reduces proven/probable IFI, IA, and IFI-related mortality in cancer patients receiving chemotherapy or HSCT, but increases AE and does not affect overall mortality. (PROSPERO Registration: CRD420111174) British Journal of Cancer (2012) 106, 1626–1637. doi:10.1038/bjc.2012.147 www.bjcancer.com & 2012 Cancer Research UK Keywords: antifungal; prophylaxis; fluconazole; infections Cancer patients receiving intensive chemotherapy or undergoing echinocandins such as caspofungin and micafungin, and ampho- haematopoietic stem cell transplantation (HSCT) are at an tericin have coverage that extends to yeasts and moulds. However, increased risk of invasive fungal infections (IFI); both yeasts and each of these agents may have specific downsides including moulds contribute to IFI in these populations (Mahfouz and toxicity, potential for drug interactions and considerable costs. Anaissie, 2003). IFI are associated with considerable morbidity and Previous randomised trials have shown the benefits of mortality. Although invasive aspergillosis (IA) has decreased in fluconazole prophylaxis when compared with placebo in patients recent years (Pagano et al, 2010), mortality remains unacceptably receiving chemotherapy and undergoing HSCT (Goodman et al, high. As a result, emphasis has been placed on prevention of IFI 1992; Slavin et al, 1995; Rotstein et al, 1999). However, individual using prophylactic strategies. trials comparing mould-active prophylaxis to fluconazole have Choices for systemic antifungal prophylaxis include fluconazole yielded inconsistent results with most studies failing to show a and agents with activity against moulds. Fluconazole is inexpen- reduction in proven or probable IFI (Wingard et al, 2010). sive and in general, well tolerated. However, it lacks activity against Consequently, there are conflicting recommendations for anti- moulds, in particular against Aspergillus spp. In contrast, newer fungal prophylaxis from published guidelines (Cornely et al, 2009; broad-spectrum azoles such as voriconazole and posaconazole, Freifeld et al, 2011), which has led to variability in clinical practice (Lehrnbecher et al, 2009). Although there are many randomised trials which assessed the efficacy of antifungal prophylaxis, most were underpowered *Correspondence: Dr L Sung; E-mail: lillian.sung@sickkids.ca to detect a significant difference in the incidence of proven or Received 7 November 2011; revised 6 March 2012; accepted 22 March probable IFI or all-cause mortality. We hypothesised that 2012 Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al including all available studies that compared mould-active vs Outcomes fluconazole prophylaxis would improve the ability to determine The primary outcome was proven or probable IFI. IFI were whether mould-active agents are associated with fewer proven or re-classified using the revised EORTC/MSG criteria when sufficient probable IFI and whether these agents are associated with a data were available and authors used other definitions (De Pauw survival benefit. The primary objective of this review was to et al, 2008). When re-classification was not possible, the study was determine whether mould-active prophylaxis reduces the inci- not included in the analysis of this outcome. A secondary outcome dence of proven or probable IFI, when compared with fluconazole. was IA that was defined as culture-proven Aspergillus or The secondary objectives were to determine whether mould-active Aspergillus diagnosed by microscopic examination (De Pauw prophylactic strategies, when compared with fluconazole, are et al, 2008). The time period for IFI and IA observation was during associated with a reduction in: (1) incidence of IA; (2) adverse the study period, which varied across studies. Other secondary events (AE) requiring discontinuation or modification of outcomes were IFI- and IA-related mortality, all-cause mortality antifungal prophylaxis; (3) number of IFI- and IA-related deaths; and adverse events leading to discontinuation or modification and (4) all-cause mortality. of study drug. The time period for observation of mortality was 3 months. We did not examine possible IFI as there was considerable inconsistency as to how this outcome was defined. METHODS The reporting of this meta-analysis follows the recommendations Data collection process of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (Moher et al, 2009). Methods of the Two reviewers (MCE and MS) independently abstracted data analysis and inclusion criteria were specified in advance from included trials using a standardised data collection form. and registered in the PROSPERO registry of systematic reviews Disagreements were resolved by discussion between the two (Ethier, 2011). reviewers; if no agreement could be reached, it was pre-specified that a third author (LS) would arbitrate. Corresponding authors were contacted to retrieve additional data if needed. Eligibility criteria The following information was extracted: (1) study character- istics (recruitment period, number of subjects, follow-up period, Randomised controlled trials comparing systemic mould-active to country where study performed, whether study was multicenter, fluconazole prophylaxis were eligible. Any of the following mould- concurrent antibiotic prophylaxis, definitions for IFI, criteria for active agents were included as long as they were administered starting and stopping prophylaxis); (2) characteristics of trial systemically: amphotericin B (conventional and lipid formula- participants (population, diagnosis, age, gender); (3) intervention tions), caspofungin, micafungin, anidulafungin, posaconazole, and comparison (name of drug, dose, route, duration, frequency); itraconazole, voriconazole, or ketoconazole. Inclusion criteria and (4) outcomes. were: (1) randomisation between systemic mould-active and fluconazole prophylaxis; and (2) patients of any age receiving chemotherapy for cancer or undergoing HSCT. We excluded Risk of bias in individual studies (1) studies in which more than one systemic prophylactic anti-fungal agent was given in one of the study arms; (2) studies that did not To assess the risk of bias, included articles were examined by two report any of the primary or secondary outcomes; and (3) studies of reviewers (MCE and MS) for: (1) generation of sequence allocation; pre-emptive or empiric therapy or anti-fungal treatment. There were (2) allocation concealment; (3) blinding; (4) incomplete outcome no restrictions by language or by publication status. data; and (5) intention-to-treat (ITT) analysis. Definitions/criteria of these items were derived from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins and Green, 2009). Information sources and search details We performed an electronic search of OVID MEDLINE (from 1948 Statistical analysis to August 2011), EMBASE (from 1980 to August 2011), and The Cochrane Central Register of Controlled Trials (CENTRAL; until The meta-analysis was performed by computing relative risks the third quarter of 2011). Searches were last updated 24 August (RRs) using a random-effects model as heterogeneity between 2011. We also reviewed the reference lists of relevant articles and trials was expected. We followed the ITT principle when we reviews as well as trials registered on the ClinicalTrials.gov calculated summary RRs with 95% confidence intervals (CI). The website. We searched for conference proceedings from 2005 to Mantel–Haenszel method was chosen as the event rates were 2011 using the Web of Science (version 4.10) as well as abstracts relatively low across all outcomes. We considered P-valueso0.05 presented within the last 2 years at annual meetings of the statistically significant. Synthesis was performed using Review American Society of Hematology and American Society of Clinical Manager (Version 5.1, The Cochrane Collaboration, 2011, http:// Oncology. ims.cochrane.org/revman/download). Meta-regression also was We used the following search terms in both indexed and text performed in addition to stratified analyses using SAS-PC software word forms to search all databases: fluconazole, Aspergillus or (version 9.2; SAS Institute, Cary, NC, USA). mycoses, prevention or prophylaxis, neoplasm or SCT or Sub-group analyses defined a priori were performed to neutropenia, with appropriate limits to identify randomised investigate the effects of age (children vs adults), study population controlled trials (Appendix Table A1 for full search strategy). (HSCT vs chemotherapy), drug used in the experimental Two reviewers (MCE and MS) assessed the title and abstract of comparison group (amphotericin vs mould-active azoles vs each reference identified by the search and applied the eligibility echinocandins), and dose of fluconazole (X400 mg per day vs criteria. For potentially relevant articles, the full article was o400 mg per day). We excluded studies that included both obtained and assessed by both authors independently. Final chemotherapy and HSCT patients from the study population sub- inclusion of studies in the meta-analysis was determined by group analysis. We also examined subgroups by blinding and ITT agreement of both reviewers. If consensus could not be reached, analysis. Outcomes identified for sub-group analyses were proven/ disagreements were resolved by a third study author (LS). probable IFI, IA, IFI-, and IA-related mortality, overall mortality Agreement between reviewers was evaluated by using the kappa and AEs requiring antifungal treatment discontinuation or statistic. modification. & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Concern has been raised about the effectiveness of itraconazole trials and serum beta-D-glucan testing in one trial (Ito et al, 2007a; capsule to prevent IFD (Prentice et al, 2006) and at least two sets of Ullmann et al, 2007; Wingard et al, 2010). guidelines have recommended against its use as prophylaxis Risk of bias assessment is presented in Table 2. The majority of (Walsh et al, 2008; Maertens et al, 2011). Consequently, we also studies did not provide adequate information on sequence conducted a sensitivity analysis excluding the two studies that used allocation and allocation concealment. Only 4 out of 20 (20%) of itraconazole capsules. There also has been concerns about whether the studies were blinded and 6 out of 20 (30%) performed an ITT doses of itraconazole solution o400 mg per day is effective analysis. (Glasmacher et al, 2003) and consequently, we conducted a second The analysis of the primary outcome, which was proven or sensitivity analysis in which we deleted studies that used doses probable IFI, encompassed 2385 (mould-active group) and 2417 lower than this threshold amount. (fluconazole group) patients, in 18 studies. When data from all 18 Heterogeneity was initially inspected graphically (forest plot) studies that reported on our primary outcome were pooled, and assessed statistically using the I statistic and by performing a mould-active compared with fluconazole prophylaxis significantly test for heterogeneity. reduced the risk of IFI (RR 0.71, 95% CI 0.52–0.98; P¼ 0.03), with We assessed the possibility of publication bias by examining moderate heterogeneity (I ¼ 33%, P¼ 0.11) as illustrated in funnel plots for asymmetry (Sutton et al, 2000). Table 3 and Figure 2. Mould-active prophylaxis, when compared with fluconazole prophylaxis, decreased the risk of IA (RR 0.53, 95% CI 0.37–0.75) RESULTS and IFI-related mortality (RR 0.67, 95% CI 0.47–0.96). However, mould-active prophylaxis was significantly associated with more A total of 984 titles and abstracts were reviewed (Figure 1); 20 were adverse events leading to antifungal prophylaxis discontinuation retrieved for detailed evaluation (Bodey et al, 1994; Annaloro et al, or modification when compared with fluconazole prophylaxis (RR 1995; Morgenstern et al, 1999a; Huijgens et al, 1999b; Timmers 1.95, 95% CI 1.24–3.07). Importantly, mould-active prophylaxis et al, 2000b; Wolff et al, 2000b; Koh et al, 2002a; Glasmacher et al, did not significantly influence overall mortality (RR 1.0, 95% CI 2003; Winston et al, 2003; Marr et al, 2004; van Burik et al, 2004; 0.88–1.13). Funnel plots were reviewed for each of the study Choi et al, 2005; Oren et al, 2006b; Cornely et al, 2007; Ito et al, outcomes. No apparent asymmetry was seen by visual assessment 2007b; Ullmann et al, 2007; Hiramatsu et al, 2008b; Sawada et al, (data not shown). 2009a; Ota et al, 2010; Wingard et al, 2010) and all 20 (19 full-text The results from the subgroup analyses for 4 of our 5 pre- articles and one conference abstract (Ota et al, 2010)) satisfied specified outcomes are presented in Table 4 and Appendix eligibility criteria and were included in the final meta-analysis. Table A3. Subgroup analysis by age was not possible as only one The kappa statistic for study inclusion was 1.0, reflecting perfect study included children only. There was no evidence for a agreement. difference in the effect of mould-active vs fluconazole prophylaxis Demographics of the 20 included studies are presented in for any of the outcomes. However, the beneficial effect of mould- Table 1. A total of 5725 patients were included in this review with active prophylaxis appeared qualitatively greater in studies of ages ranging from 0.6 to 82 years. Trials were performed in Asia other azoles and echinocandins in comparison with amphotericin (n¼ 7), Europe (n¼ 5), North America (n¼ 5), and internationally B formulations. There was no evidence that the effect of mould- (n¼ 3). Half of the studies were multi-centred (10 out of 20, active prophylaxis differed by blinding status or application of the 50.0%). The patient populations were HSCT (n¼ 14) and ITT principle (Appendix Table A2). The results from the meta- chemotherapy (n¼ 6). Children were included in four trials but regression are presented in Appendix Table A4 and are consistent only one trial comprised of children only. Antibiotic prophylaxis with the results from the sub-group analysis. was recommended in 8 out of 20 (40%) of trials. Study regimens Appendix Table A5 illustrates the sensitivity analyses that included amphotericin B formulations (n¼ 4), micafungin (n¼ 3), removed the two studies of itraconazole capsule prophylaxis and posaconazole (n¼ 2), voriconazole (n¼ 1), and itraconazole the three studies that used oral itraconazole solution doses (n¼ 10). All studies of echinocandins consisted of micafungin. o400 mg per day. The removal of these studies did not impact Fungal prophylaxis was started either with the initiation of the results, with the exception of proven or probably IFI which was chemotherapy (n¼ 18) or at the onset of neutropenia (n¼ 1; no longer significant after removing the three studies that used Sawada et al, 2009a), and was not available for one study (Choi oral itraconazole solution doses o400 mg per day. et al, 2005). Routine galatomannan testing was performed in two DISCUSSION Potentially eligible studies We found that in patients with cancer receiving chemotherapy or identified by the search HSCT, mould-active prophylaxis when compared with fluconazole strategy prophylaxis was associated with a clinically relevant reduction in (n = 984) proven or probable IFI, IA and IFI-related mortality. However, Excluded by review of title and abstract (n = 964) mould-active prophylaxis was also associated with a significantly Did not fulfill inclusion / exclusion increased risk of adverse events requiring discontinuation or criteria modification of therapy and did not affect overall mortality. (n = 750) These results are in keeping with those from a previous review Duplicate publication (n = 214) comparing mould-active to fluconazole prophylaxis that was Full articles retrieved for conducted as a sub-group analysis of a large review; this review detailed evaluation included studies published up to 2007 (Robenshtok et al, 2007). (n = 20) Similar to our study, that review found that mould-active prophylaxis significantly reduced documented IFI, IA, and IFI- related mortality, and did not impact on all-cause mortality. Our Studies included in meta- results provide important new information since six new trials analysis comparing fluconazole to systemic mould-active prophylaxis were (n = 20) added (Choi et al, 2005; Ito et al, 2007a; Hiramatsu et al, 2008a; Figure 1 Flow diagram of trial identification and selection. Sawada et al, 2009b; Ota et al, 2010; Wingard et al, 2010), which British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table 1 Characteristics of included trials that compare fluconazole vs mould-active antifungal prophylaxis Surro- Multi- gate Study author Pub year centre N Population Mould-active dose Fluconazole dose Prophylaxis end testing 1  1 Bodey et al, 1994 1994 No 77 Hem malignancy CAB 0.17 mg kg per dose 400 mg per dose PO/IV ANC41000 ml or 8 No IV TID OD weeks Annaloro et al, 1995 No 59 HSCT (auto, allo) Itraconazole 400 mg per dose 300 mg per dose PO OD Neutropenia resolution No 1995 PO OD Huijgens et al, 1999 No 202 Hem malignancy, HSCT Itraconazole 100 mg per dose 50 mg per dose PO BID ANC4500 ml No 1999a (auto) PO BID 1  1 Morgenstern 1999 Yes 581 Hem malignancy, HSCT Itraconazole 2.5 mg kg per 100 mg per dose PO OD ANC41000 ml  7 No et al, 1999b (auto, allo) dose PO BID days Timmers et al, 2000 No 24 Hem malignancy, HSCT Amphotericin B colloidal 200 mg per dose PO OD ANC4500 ml No 2000a (auto, allo) dispersion 2 mg kg per dose IV OD 1  1 Wolff et al, 2000 Yes 355 HSCT (auto, allo) CAB 0.2 mg kg per dose IV 400 mg per dose PO/IV ANC4500 ml No 2000a OD OD 1  1 Koh et al, 2002b 2002 No 186 HSCT (auto, allo) CAB 0.2 mg kg per dose IV 200 mg per dose PO OD ANC4500 ml  3 No OD days Winston et al, 2003 Yes 138 HSCT (allo) Itraconazole 200 mg per dose 400 mg per dose IV Dþ 100 No 2003 IV BID 4 then 200 mg per OD 14 then 400 mg dose IV OD 12 then 200 mg per dose PO OD until per dose PO BID until Dþ 100 Dþ 100 Marr et al, 2004 2004 No 299 HSCT (allo) Itraconazole 2.5 mg kg per 400 mg per dose PO/IV Dþ 120–180 days No dose PO TID or 200 mg per OD dose IV OD van Burik et al, 2004 Yes 882 HSCT (auto, allo) Micafungin 50 mg per dose IV 400 mg per dose IV OD ANCX500 ml  5 No 2004 OD days or Dþ 42 Choi et al, 2005 2005 No 78 HSCT (allo) Itraconazole 200 mg per dose 200 mg per dose PO OD NS No PO OD 1  1 Glasmacher et al, 2006 Yes 494 Hem malignancy Itraconazole 5 mg kg per 400 mg per dose PO/IV ANC41000 ml or 8 No 2006 dose PO BID OD weeks Oren et al, 2006a 2006 No 195 Hem malignancy, HSCT Itraconazole 200 mg per dose 400 mg per dose PO/IV Neutropenia resolution or No (auto, allo) PO/IV BID OD 8 weeks Cornely et al, 2007 Yes 544 Hem malignancy Posaconazole 200 mg per 400 mg per dose PO/IV Neutropenia resolution or No 2007 dose PO/IV BID OD 12 weeks Ito et al, 2007a 2007 Yes 209 Hem malignancy Itraconazole 200 mg per dose 200 mg per dose PO OD ANC 41000 ml or Yes PO OD leukocytesX2 ml Ullmann et al, 2007 Yes 600 GVHD Posaconazole 200 mg per 400 mg per dose PO OD 112 days Yes 2007 dose PO TID Hiramatsu et al, 2008 No 100 HSCT (auto, allo) Micafungin 150 mg per dose IV 400 mg per dose IV OD ANC4500 ml 5or No 2008a OD Dþ 42 1  1  1 Sawada et al, 2009 Yes 107 Hem malignancy, HSCT Micafungin 2 mg kd per 10 mg kg per dose IV ANC4500 ml No 2009b (allo/auto) dose IV OD OD Ota et al, 2010 2010 No 73 HSCT (auto, allo) Itraconazole 200 mg per dose 400 mg per dose PO/IV Dþ 28 No PO/IV OD OD Wingard et al, 2010 Yes 600 HSCT (allo) Voriconazole 200 mg per dose 400 mg per dose PO OD Dþ 100 Yes 2010 PO BID Abbreviations: allo¼ allogeneic; ANC¼ absolute neutrophil count; auto¼ autologous; BID¼ twice daily; CAB¼ conventional amphotericin B; D¼ day of HSCT; GVHD¼ graft- vs-host disease; Hem¼ haematological; HSCT¼ haematopoietic stem cell transplantation; IV¼ intravenous; N¼ total number of subjects randomised; NS¼ not specified; OD¼ once daily; Pub¼ publication; PO¼ oral; TID¼ three times daily. Surrogate marker evaluation for invasive fungal infection includes galactomannin and beta-D glucan testing. Table 2 Risk of bias assessment of included articles Adequate Adequate Description of Selective sequence allocation withdrawals Intention to outcome Study author generation concealment Blinding and dropouts treat analysis report Bodey et al, 1994 Yes Unclear No Yes No No Annaloro et al, 1995 Unclear Unclear No No Yes No Huijgens et al, 1999a Unclear Unclear Yes Yes No No Morgenstern et al, 1999b Yes Inadequate No No No Yes Timmers et al, 2000a Unclear Unclear No No No No Wolff et al, 2000a Unclear Unclear No No Yes No Koh et al, 2002b Unclear Unclear No No Yes No Winston et al, 2003 Unclear Yes No Yes No No Marr et al, 2004 Unclear Unclear No Yes No No van Burik et al, 2004 Yes Yes Yes Yes No No Choi et al, 2005 Unclear Unclear No No No No Glasmacher et al, 2006 Yes Yes No Yes No No Oren et al, 2006a Yes Unclear No No No No Cornely et al, 2007 Unclear Unclear No No Yes No Ito et al, 2007a Yes Unclear No Yes No No Ullmann et al, 2007 Unclear Unclear Yes No Yes No Hiramatsu et al, 2008a Unclear Unclear No Yes No No Sawada et al, 2009b Unclear Yes No No No No Ota et al, 2010 Unclear Unclear No No No Wingard et al, 2010 Yes Yes Yes Yes Yes No & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table 3 Synthesised primary and secondary outcomes of mould-active vs fluconazole prophylaxis Outcome Trials (patients) RR (95% CI) P-value Proven or probable IFI 18 (4802) 0.71 (0.52, 0.98) 0.03 Invasive aspergillosis 15 (4503) 0.53 (0.37, 0.75) 0.0004 Adverse events requiring antifungal treatment discontinuation or modification 16 (4493) 1.95 (1.24, 3.07) 0.004 IFI-related mortality 15 (4272) 0.67 (0.47, 0.96) 0.03 Invasive aspergillosis-related mortality 9 (2614) 0.62 (0.23, 1.71) 0.36 Overall mortality 16 (4870) 1.00 (0.88, 1.13) 0.96 Abbreviations: CI¼ confidence interval; IFI¼ invasive fungal infection; RR¼ risk ratio. RRo1 represents an advantage of mould-active coverage using a random-effects model. Mould-active Fluconazole Risk ratio Risk ratio Weight Study or subgroup Events Total Events Total (%) M-H, random, 95% Cl Year M – H, random, 95% Cl Bodey (1994) 10 36 5 41 7.3 2.28 (0.86, 6.04) 1994 Annaloro (1995) 4 31 128 2.0 3.61 (0.43, 30.43) 1995 Huijgens (1999) 4 101 4 101 4.4 1.00 (0.26, 3.89) 1999 Timmers (2000) 0 12 0 12 Not estimable 2000 Koh (2002) 11 86 12 100 9.9 1.07 (0.50, 2.29) 2002 Winston (2003) 6 71 17 67 8.5 0.33 (0.14, 0.79) 2003 Marr (2004) 20 151 25 148 14.0 0.78 (0.46, 1.35) 2004 van Burik (2004) 7 425 11 457 7.7 0.68 (0.27, 1.75) 2004 Choi (2005) 0 40 0 38 Not estimable 2005 Glasmacher (2006) 4 248 5 246 4.7 0.79 (0.22, 2.92) 2006 Oren (2006) 8 96 9 99 8.0 0.92 (0.37, 2.28) 2006 Cornely (2007) 4 239 19 240 6.4 0.21 (0.07, 0.61) 2007 Ulmann (2007) 16 301 27 299 12.8 0.59 (0.32, 1.07) 2007 Ito (2007) 0 103 3 106 1.1 0.15 (0.01, 2.81) 2007 Hiramatsu (2008) 1 50 1 50 1.3 1.00 (0.06, 15.55) 2008 Sawada (2009) 0 54 0 53 Not estimable 2009 Wingard (2010) 14 305 24 295 12.0 0.56 (0.30, 1.07) 2010 Ota (2010) 0 36 0 37 Not estimable 2010 Total (95% Cl) 2385 2417 100.0 0.71 (0.52, 0.98) Total events 109 163 2 2 2 Heterogeneity:  = 0.11;  = 19.53, df = 13 (P =0.11); I = 33% 0.01 0.1 1 10 100 Test for overall effect: Z = 2.11 (P = 0.03) Favours mould-active Favours fluconazole Figure 2 Forest plot of effect of mould-active vs fluconazole prophylaxis on the primary outcome, proven or probable invasive fungal infection. Squares to the left of the vertical line indicate a decreased risk of developing an event in patients receiving mould-active prophylaxis. Horizontal lines through the squares represent 95% CIs. The diamonds represents the overall RR from the meta-analyses and the corresponding 95% CIs. allowed more precise estimation of the effect of mould-active a small proportion of overall mortality within this time frame in prophylaxis on overall mortality. Furthermore, we examined an these populations. The second possibility that may explain the additional clinically important outcome, namely adverse events discrepancy between a reduction in IFD incidence and no effect on resulting in discontinuation of antifungal prophylaxis, which overall mortality may relate to the use of galactomannan tests provides more information to judge the overall utility of mould- (Marr et al, 2005). Mould-active agents are known to reduce the active prophylaxis. sensitivity of this test and thus, it is possible that the reduction in We found that mould-active prophylaxis, when compared with IFD seen with anti-mould agents is actually spurious. The third fluconazole prophylaxis, reduces IFI-related mortality but does not possibility is that mould-active prophylaxis increases non-IFI- influence overall mortality with a point estimate RR of 1.0. The related deaths. This hypothesis is supported by the increase in 95% CI around the overall mortality estimate does not exclude adverse events observed in the mould-active prophylaxis arm. clinically meaningful benefit or harm since the interval was Furthermore, it is possible that drug interactions further 0.88–1.13. As IFI-related mortality is a component of overall contributed to increased patient deaths. mortality, it is interesting to see discordance in these two results. There are at least three downsides of mould-active antifungal There are at least three possibilities to explain this discordance. prophylaxis. First, mould-active prophylaxis may be associated First, the proportion of IFI-related mortality could be such a small with increased adverse events compared with fluconazole prophy- portion of overall mortality that reductions in IFI-related mortality laxis as we have demonstrated. Second, mould-active prophylaxis may not detectably impact on mortality. However, there are two with non-fluconazole azoles may be associated with significant observations that argue against this hypothesis. First, the point drug interactions and the impact of these interactions has not been estimate for overall mortality was 1.0, which suggests no reduction fully evaluated. Third is the issue of costs. Many of the mould- in mortality. Second, mortality was observed for only 3 months active agents are associated with large costs given the duration of and thus, it is hard to envision that IFI-related mortality would be prophylaxis for patients with leukaemia or undergoing allogeneic British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al prophylaxis may be lower (Lehrnbecher et al, 2008). In contrast, Table 4 Stratified analyses by mould-active agent amphotericin B formulations and echinocandins are only available P-value in parenteral formulation and, thus, their administration in a for a prophylactic manner would be expected to have a sizeable impact Trials RR interaction Outcome (patients) (95% CI) P-value test on quality of life. This study has several limitations. First and most importantly, Mould-active agent we combined several different classes of mould-active antifungals Proven or probable IFI 0.1 that are expected to have different efficacy and toxicity profiles. Amphotericin 3 (287) 1.46 (0.70, 3.05) 0.31 Other azoles 12 (3426) 0.60 (0.43, 0.84) 0.003 However, the stratified analysis failed to illustrate important Echinocandin 3 (1089) 0.71 (0.29, 1.73) 0.45 differences in outcome by mould-active antifungal class. Second, fungal classification and reporting was not consistent in the studies Invasive aspergillosis 0.29 Amphotericin 3 (618) 1.18 (0.28, 4.97) 0.82 included although we attempted to address this limitation by Other azoles 9 (2796) 0.52 (0.36, 0.76) 0.0006 re-classifying infections using the EORTC/MSG definitions for IFI Echinocandin 3 (1089) 0.19 (0.03, 1.11) 0.07 (Ascioglu et al, 2002). Third, it is possible that surveillance for IFI IFI-related mortality using galactomannan and beta-D-glucan testing may have altered Amphotericin 4 (642) 0.91 (0.39, 2.16) 0.83 the efficacy of mould-active prophylaxis. There are an insufficient Other azoles 9 (2648) 0.64 (0.38, 1.08) 0.09 number of studies that used such testing to be able to explore this Echinocandin 2 (982) 0.70 (0.12, 4.28) 0.70 effect. Finally, it is also important to mention that only one study IA-related mortality 0.43 included children only, and thus, we are unable to determine if the Amphotericin 2 (101) 3.41 (0.14, 81.07) 0.45 effect of mould-active prophylaxis compared with fluconazole Other azoles 5 (1531) 0.63 (0.18, 2.13) 0.46 Echinocandin 2 (982) 0.27 (0.03, 2.38) 0.24 differs between children and adults. This deficiency supports the need for future randomised trials in children in order determine Overall mortality 0.79 the effect of mould-active prophylaxis in paediatrics. Amphotericin 3 (618) 1.11 (0.78, 1.59) 0.55 Other azoles 11 (3270) 0.99 (0.86, 1.14) 0.89 Future studies should attempt to better describe the potential Echinocandin 2 (982) 0.89 (0.42, 1.88) 0.76 benefits and downsides of mould-active prophylaxis. This may be accomplished through future randomised trials of agents thought AEs requiring antifungal 0.001 treatment discontinuation to be less toxic and through individual patient-level meta-analyses. or modification Furthermore, patient preferences and costs deserve future Amphotericin 4 (642) 5.98 (1.20, 29.86) 0.03 exploration. Mould-active antifungal prophylaxis may have a large Other azoles 10 (2869) 1.92 (1.19, 3.08) 0.007 Echinocandin 2 (982) 0.59 (0.34, 1.03) 0.06 economic impact on care of patients with haematological malignancy and undergoing HSCT; we must be relatively certain Abbreviations: AEs¼ adverse events; CI¼ confidence interval; IA¼ invasive asper- a of benefits before routine implementation. gillosis; IFI¼ invasive fungal infection; RR¼ risk ratio. RRo1 represents an advantage In conclusion, this meta-analysis demonstrates that prophylaxis of mould-active coverage compared with fluconazole using a random-effects model. with mould-active compared with fluconazole prophylaxis significantly reduces the number of proven or probable IFI, IA, and IFI-related mortality in patients receiving chemotherapy or HSCT. Cost-effectiveness analyses have shown that posaconazole is undergoing HSCT. However, mould-active antifungal prophylaxis a cost-effective strategy for preventing IFI, compared with also increases adverse events leading to antifungal modification or fluconazole, in patients with GVHD and with acute myeloid discontinuation and does not impact on overall mortality. Future leukaemia/myelodysplastic syndrome (Stam et al, 2008; de la work to better understand the benefits and downsides of individual Camara et al, 2010; Dranitsaris and Khoury, 2011). In adult classes of mould-active antifungals and to explore patient patients undergoing HSCT, micafungin has been shown to reduce preferences and costs is warranted. hospital costs and total patient costs (Schonfeld et al, 2008) and to be cost effective (Sohn et al, 2009), compared with fluconazole. However, these analyses have been based upon single studies rather than synthesised results. Further exploration of costs that ACKNOWLEDGEMENTS take into consideration patient preferences are warranted. Finally, there has been little evaluation of patient preferences for antifungal We would like to thank Ryoko Ingram who generously assisted prophylaxis. Agents such as posaconazole, voriconazole and with the translation of the article by Sawada into English, as well as itraconazole have an oral formulation and thus, may have a lesser Elizabeth Uleryk who provided invaluable feedback for the impact on quality of life given that administration may occur systematic literature search. LS is supported by a New Investigator on an outpatient basis. However, compliance of oral antifungal Award with the Canadian Institutes of Health Research. REFERENCES Annaloro C, Oriana A, Tagliaferri E, Bertolli V, Della Volpe A, Soligo D, Bodey GP, Anaissie EJ, Elting LS, Estey E, O’Brien S, Kantarjian H (1994) Ibatici A, Pozzoli E, Lambertenghi Deliliers GL (1995) Efficacy of Antifungal prophylaxis during remission induction therapy for acute different prophylactic antifungal regimens in bone marrow transplanta- leukemia fluconazole versus intravenous amphotericin B. Cancer 73(8): tion. Haematologica 80(6): 512–517 2099–2106 Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Choi SM, Lee DG, Choi JH, Park SH, Eom KS (2005) Itraconazole oral Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, solution versus fluconazole syrup for prevention of invasive fungal Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh infections in patients receiving hematopoietic stem cell transplantation: TJ. Invasive Fungal Infections Cooperative Group of the European prospective, randomized, comparative clinical trial. Infect Chemother Organization for R, Treatment of CMycoses Study Group of the National 37(2): 71–78 Institute of A, Infectious D (2002) Defining opportunistic invasive fungal Cornely OA, Bohme A, Buchheidt D, Einsele H, Heinz WJ, Karthaus M, infections in immunocompromised patients with cancer and hemato- Krause SW, Kruger W, Maschmeyer G, Penack O, Ritter J, Ruhnke M, poietic stem cell transplants: an international consensus. Clin Infect Sandherr M, Sieniawski M, Vehreschild JJ, Wolf HH, Ullmann AJ. Diseas 34(1): 7–14 Recommendations of the Infectious Diseases Working Party of the & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al German Society for Haematology and Oncology (2009) Primary Huijgens PC, Simoons-Smit AM, van Loenen AC, Prooy E, van Tinteren H, prophylaxis of invasive fungal infections in patients with hematologic Ossenkoppele GJ, Jonkhoff AR (1999b) Fluconazole versus malignancies. Haematologica 94(1): 113–122 itraconazole for the prevention of fungal infections in haemato-oncology. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, J Clin Pathol 52(5): 376–380 Helfgott D, Holowiecki J, Stockelberg D, Goh Y-T, Petrini M, Hardalo C, Ito Y, Ohyashiki K, Yoshida I, Takeuchi M, Aoyama Y, Mugitani A, Suresh R, Angulo-Gonzalez D (2007) Posaconazole vs fluconazole or Matsuura Y, Wakita H, Matsuda M, Sakamoto E, Kiguchi T, Urabe A, itraconazole prophylaxis in patients with neutropenia. N Engl J Med Tamura K, Kanamaru A, Masaoka T (2007a) The prophylactic effect of 356(4): 348–359 itraconazole capsules and fluconazole capsules for systemic fungal de la Camara R, Jarque I, Sanz MA, Grau S, Casado MA, Sabater FJ, infections in patients with acute myeloid leukemia and myelodysplastic Carreras E (2010) Economic evaluation of posaconazole vs fluconazole in syndromes: a Japanese multicenter randomized, controlled study the prevention of invasive fungal infections in patients with GVHD Int J Hematol 85(2): 121–127 following haematopoietic SCT. Bone Marrow Transplant 45(5): 925–932 Ito Y, Ohyashiki K, Yoshida I, Takeuchi M, Aoyama Y, Mugitani A, De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Matsuura Y, Wakita H, Matsuda M, Sakamoto E, Kiguchi T, Urabe A, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Tamura K, Kanamaru A, Masaoka T (2007b) The prophylactic effect of Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R itraconazole capsules and fluconazole capsules for systemic fungal Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Munoz P, Odds FC, infections in patients with acute myeloid leukemia and myelodysplastic Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli syndromes: a Japanese multicenter randomized, controlled study C, Wingard JR, Zaoutis T, Bennett JE. European Organization for R, Int J Hematol 85(2): 121–127 Treatment of Cancer/Invasive Fungal Infections Cooperative GNational Koh LP, Kurup A, Goh YT, Fook-Chong SMC, Tan PHC (2002a) Institute of AInfectious Diseases Mycoses Study Group Consensus G Randomized trial of fluconazole versus low-dose amphotericin B in (2008) Revised definitions of invasive fungal disease from the European prophylaxis against fungal infections in patients undergoing hemato- Organization for Research and Treatment of Cancer/Invasive Fungal poietic stem cell transplantation. Am J Hematol 71(4): 260–267 Infections Cooperative Group and the National Institute of Allergy and Koh LP, Kurup A, Goh YT, Fook-Chong SMC, Tan PHC (2002b) Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Randomized trial of fluconazole versus low-dose amphotericin B in Group. Clin Infect Dis 46(12): 1813–1821 prophylaxis against fungal infections in patients undergoing hemato- Dranitsaris G, Khoury H (2011) Posaconazole versus fluconazole or poietic stem cell transplantation. J Clin Pathol 71(4): 260–267 itraconazole for prevention of invasive fungal infections in patients Lehrnbecher T, Ethier MC, Zaoutis T, Creutzig U, Gamis A, Reinhardt D, undergoing intensive cytotoxic therapy for acute myeloid leukemia or Aplenc R, Sung L (2009) International variations in infection supportive myelodysplasia: a cost effectiveness analysis. Support Care Cancer 19(11): care practices for paediatric patients with acute myeloid leukaemia 1807–1813 Br J Haematol 147(1): 125–128 Ethier MC (2011) Fluconazole Compared to Anti-Mold Coverage for Lehrnbecher T, Laws HJ, Boehm A, Dworzak M, Janssen G, Simon A, Groll Antifungal Prophylaxis to Prevent Invasive Fungal Infections in Cancer AH (2008) Compliance with anti-infective preventive measures: a Patients receiving Chemotherapy or after Hematopoietic Stem-Cell multicentre survey among paediatric oncology patients. Eur J Cancer Transplantation: A Systematic Review and Meta-Analysis of Randomized 44(13): 1861–1865 Controlled Trials PROSPERO: International prospective register of Maertens J, Marchetti O, Herbrecht R, Cornely OA, Fluckiger U, Frere P, systematic reviewsCRD420111174. http://www.crd.york.ac.uk/prospero/) Gachot B, Heinz WJ, Lass-Florl C, Ribaud P, Thiebaut A, Cordonnier C. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad, Third European Conference on Infections in L (2011) European Rolston KV, Young JA, Wingard JR (2011) Clinical practice guideline for guidelines for antifungal management in leukemia and hematopoietic the use of antimicrobial agents in neutropenic patients with cancer: 2010 stem cell transplant recipients: summary of the ECIL 3—2009 update. update by the Infectious Diseases Society of America. Clin Infect Dis Bone Marrow Transplant 46(5): 709–718 52(4): 427–431 Mahfouz T, Anaissie E (2003) Prevention of fungal infections Glasmacher A, Cornely O, Ullmann AJ, Wedding U, Bodenstein H, Wandt in the immunocompromised host. Curr Opin Investig Drugs 4(8): H, Boewer C, Pasold R, Wolf H-H, Hanel M, Dolken G, Junghanss C, 974–990 Andreesen R, Bertz H. Itraconazole Research Group of G (2006) An Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA open-label randomized trial comparing itraconazole oral solution with Nichols WG, Musher B, Corey L (2004) Itraconazole versus fluconazole fluconazole oral solution for primary prophylaxis of fungal infections in for prevention of fungal infections in patients receiving allogeneic stem patients with haematological malignancy and profound neutropenia cell transplants. Blood 103(4): 1527–1533 J Antimicrob Chemother 57(2): 317–325 Marr KA, Laverdiere M, Gugel A, Leisenring W (2005) Antifungal therapy Glasmacher A, Prentice A, Gorschluter M, Engelhart S, Hahn C, Djulbegovic decreases sensitivity of the Aspergillus galactomannan enzyme immu- B, Schmidt-Wolf IG (2003) Itraconazole prevents invasive fungal infections noassay. Clin Infect Dis 40(12): 1762–1769 in neutropenic patients treated for hematologic malignancies: evidence Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred from a meta-analysis of 3597 patients. J Clin Oncol 21(24): 4615–4626 reporting items for systematic reviews and meta-analyses: the PRISMA Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B statement. Ann Int Med 151(4): 264–269 Kaizer H, Shadduck RK, Shea TC, Stiff P, Friedman DJ (1992) A Morgenstern GR, Prentice AG, Prentice HG, Ropner JE, Schey SA, Warnock controlled trial of fluconazole to prevent fungal infections in patients DW. U.K. Multicentre Antifungal Prophylaxis Study Group (1999a) A undergoing bone marrow transplantation. N Engl J Med 326(13): 845–851 randomized controlled trial of itraconazole versus fluconazole for the Higgins J, Green S (2009) Cochrane Handbook for Systematic Reviews of prevention of fungal infections in patients with haematological Interventions Version 5.0.2 (updated September 2009). The Cochrane malignancies. Br J Haematol 105(4): 901–911 Collaboration 34(18): 1929–1941 Morgenstern GR, Prentice AG, Prentice HG, Ropner JE, Schey SA, Warnock Hiramatsu Y, Maeda Y, Fujii N, Saito T, Nawa Y, Hara M, Yano T, Asakura DW. U.K. Multicentre Antifungal Prophylaxis Study Group (1999b) A S, Sunami K, Tabayashi T, Miyata A, Matsuoka K-i, Shinagawa K, Ikeda randomized controlled trial of itraconazole versus fluconazole for the K, Matsuo K, Tanimoto M, West-Japan H, Oncology G (2008a) Use of prevention of fungal infections in patients with haematological micafungin versus fluconazole for antifungal prophylaxis in neutropenic malignancies. Br J Haematol 105(4): 901–911 patients receiving hematopoietic stem cell transplantation. Int J Hematol Oren I, Rowe JM, Sprecher H, Tamir A, Benyamini N, Akria L, Gorelik A, 88(5): 588–595 Dally N, Zuckerman T, Haddad N, Fineman R, Dann EJ (2006a) A Hiramatsu Y, Maeda Y, Fujii N, Saito T, Nawa Y, Hara M, Yano T prospective randomized trial of itraconazole vs fluconazole for the Asakura S, Sunami K, Tabayashi T, Miyata A, Matsuoka K-i, Shinagawa prevention of fungal infections in patients with acute leukemia and K, Ikeda K, Matsuo K, Tanimoto M, West-Japan H, Oncology G (2008b) hematopoietic stem cell transplant recipients. Bone Marrow Transplant Use of micafungin versus fluconazole for antifungal prophylaxis in 38(2): 127–134 neutropenic patients receiving hematopoietic stem cell transplantation. Oren I, Rowe JM, Sprecher H, Tamir A, Benyamini N, Akria L, Gorelik A, Int J Hematol 88(5): 588–595 Dally N, Zuckerman T, Haddad N, Fineman R, Dann EJ (2006b) A Huijgens PC, Simoons-Smit AM, van Loenen AC, Prooy E, van Tinteren H, prospective randomized trial of itraconazole vs fluconazole for the Ossenkoppele GJ, Jonkhoff AR (1999a) Fluconazole versus itraconazole prevention of fungal infections in patients with acute leukemia and for the prevention of fungal infections in haemato-oncology. J Clin hematopoietic stem cell transplant recipients. Bone Marrow Transplant Pathol 52(5): 376–380 38(2): 127–134 British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Ota S, Matsukawa T, Kosugi M, Shima K, Katsura Y, Kanaya M, Matsuoka prophylaxis in high risk neutropenic patients in the Netherlands. Eur J S, Noguchi S, Fujii S, Nakata M, Imai K, Hirano T, Kobayashi N, Haematol 81(6): 467–474 Ogasawara M, Kiyama Y, Kasai M (2010) Itraconazole versus fluconazole Sutton AJ, Duval SJ, Tweedie RL, Abrams KR, Jones DR (2000) Empirical for prophylaxis against invasive fungal infections during neutropenia in assessment of effect of publication bias on meta-analyses. BMJ 320(7249): patients receiving haematopoietic stem cell transplants. Bone Marrow 1574–1577 Transplant. Conference: 36th Annual Meeting of the European Group for Timmers GJ, Zweegman S, Simoons-Smit AM, van Loenen AC, Touw D, Blood and Marrow Transplantation, EBMT 2010 Vienna Austria. Huijgens PC (2000a) Amphotericin B colloidal dispersion (Amphocil) vs Conference Start: 20100321 Conference End: 20100324. Conference fluconazole for the prevention of fungal infections in neutropenic Publication: (var.pagings) 45: S394 patients: data of a prematurely stopped clinical trial. Bone Marrow Pagano L, Caira M, Candoni A, Offidani M, Martino B, Specchia G, Transplant 25(8): 879–884 Pastore D, Stanzani M, Cattaneo C, Fanci R, Caramatti C, Rossini F, Timmers GJ, Zweegman S, Simoons-Smit AM, van Loenen AC, Touw D, Luppi M, Potenza L, Ferrara F, Mitra ME, Fadda RM, Invernizzi R, Aloisi Huijgens PC (2000b) Amphotericin B colloidal dispersion (Amphocil) vs T, Picardi M, Bonini A, Vacca A, Chierichini A, Melillo L, de Waure C, fluconazole for the prevention of fungal infections in neutropenic Fianchi L, Riva M, Leone G, Aversa F, Nosari A (2010) Invasive patients: data of a prematurely stopped clinical trial. Bone Marrow aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 Transplantation 25(8): 879–884 registry study. Haematologica 95(4): 644–650 Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo Prentice AG, Glasmacher A, Djulbegovic B (2006) In meta-analysis SR, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, itraconazole is superior to fluconazole for prophylaxis of systemic Patino H, Durrant S (2007) Posaconazole or fluconazole for prophylaxis fungal infection in the treatment of haematological malignancy. Br J in severe graft-versus-host disease. [Erratum appears in N Engl J Med. Haematol 132(5): 656–658 2007 Jul 26;357(4):428] N Engl J Med 356(4): 335–347 Robenshtok E, Gafter-Gvili A, Goldberg E, Weinberger M, Yeshurun M, van Burik J-AH, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Leibovici L, Paul M (2007) Antifungal prophylaxis in cancer patients Vesole DH, Bunin N, Wall DA, Hiemenz JW, Satoi Y, Lee JM, Walsh TJ. after chemotherapy or hematopoietic stem-cell transplantation: systema- National Institute of AInfectious Diseases Mycoses Study G (2004) tic review and meta-analysis. J Clin Oncol 25(34): 5471–5489 Micafungin versus fluconazole for prophylaxis against invasive fungal Rotstein C, Bow EJ, Laverdiere M, Ioannou S, Carr D, Moghaddam N. The infections during neutropenia in patients undergoing hematopoietic Canadian Fluconazole Prophylaxis Study Group (1999) Randomized stem cell transplantation. Clin Infect Dis 39(10): 1407–1416 placebo-controlled trial of fluconazole prophylaxis for neutropenic Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr cancer patients: benefit based on purpose and intensity of cytotoxic KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik JA, therapy. Clin Infect Dis 28(2): 331–340 Wingard JR, Patterson TF. Infectious Diseases Society of A (2008) Sawada A, Sakata N, Higuchi B, Takeshita Y, Ishihara T, Sakata A, Kouroki Treatment of aspergillosis: clinical practice guidelines of the Infectious M, Kondo O, Koyama M, Hirano S, Yasui M, Inoue M, Yoshioka A, Kawa Diseases Society of America. Clin Infect Dis 46(3): 327–360 K (2009a) Comparison of micafungin and fosfluconazole as prophylaxis Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten for invasive fungal infection during neutropenia in children undergoing ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, chemotherapy and hematopoietic stem cell transplantation. Rinsho Bolanos-Meade J, Brown J, Dipersio JF, Boeckh M, Marr KA. Blood, Ketsueki—Japanese J Clin Hematol 50(12): 1692–1699 Marrow Transplant Clinical Trials N (2010) Randomized, double-blind Sawada A, Sakata N, Higuchi B, Takeshita Y, Ishihara T, Sakata A, Kouroki trial of fluconazole versus voriconazole for prevention of invasive fungal M, Kondo O, Koyama M, Hirano S, Yasui M, Inoue M, Yoshioka A, Kawa infection after allogeneic hematopoietic cell transplantation. Blood K (2009b) Comparison of micafungin and fosfluconazole as prophylaxis 116(24): 5111–5118 for invasive fungal infection during neutropenia in children undergoing Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, chemotherapy and hematopoietic stem cell transplantation. Rinsho Blumer JL, Leitz GJ, Territo MC (2003) Intravenous and oral itraconazole Ketsueki 50(12): 1692–1699 versus intravenous and oral fluconazole for long-term antifungal Schonfeld W, Wang Cheng J, Tong KB, Seifeldin R (2008) Cost-effectiveness prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. analysis of antifungal prophylaxis in patients undergoing hematopoietic A multicenter, randomized trial. Ann Int Med 138(9): 705–713 stem cell transplantation. Clin Ther 30(5): 964–973 Wolff SN, Fay J, Stevens D, Herzig RH, Pohlman B, Bolwell B, Lynch J, Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR, Ericson S, Freytes CO, LeMaistre F, Collins R, Pineiro L, Greer J, Stein R, Meyers JD, Bowden RA (1995) Efficacy and safety of fluconazole Goodman SA, Dummer S (2000a) Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone prophylaxis for fungal infections after marrow transplantation— a prospective, randomized, double-blind study. J Infect Dis 171(6): marrow transplantation: a study of the North American Marrow 1545–1552 Transplant Group. Bone Marrow Transplant 25(8): 853–859 Sohn HS, Lee TJ, Kim J, Kim D (2009) Cost-effectiveness analysis of Wolff SN, Fay J, Stevens D, Herzig RH, Pohlman B, Bolwell B, Lynch J, micafungin versus fluconazole for prophylaxis of invasive fungal Ericson S, Freytes CO, LeMaistre F, Collins R, Pineiro L, Greer J, Stein R, infections in patients undergoing hematopoietic stem cell transplanta- Goodman SA, Dummer S (2000b) Fluconazole vs low-dose amphotericin tion in Korea. Clin Ther 31(5): 1105–1115, discussion 1066-1068 B for the prevention of fungal infections in patients undergoing bone Stam WB, O’Sullivan AK, Rijnders B, Lugtenburg E, Span LF, Janssen JJ, marrow transplantation: a study of the North American Marrow Jansen JP (2008) Economic evaluation of posaconazole vs standard azole Transplant Group. Bone Marrow Transplant 25(8): 853–859 & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al APPENDIX Table A1 Search strategies used to identify randomised study of mould-active vs fluconazole antifungal prophylaxis in patients with cancer or undergoing haematopoietic stem cell transplantation # Searches Results Ovid MEDLINE(R) 1948 to August (week 2) 2011 (run on August 24, 2011) 1 Fluconazole/ or (fluconazol* or flucolich or arnazole or beagyne or elazor or flucobeta or solacap or diflucan or triflucan or 13 405 ‘uk 49858’ or uk49858 or neofomiral or lavisa or zonal or ‘fluc hexal’ or fluchexal or oxifungol or fungata or loitin or flunazul or zoltrix).mp. 2 exp Aspergillus/pc or (exp Aspergillus/ and (prophyla* or prevent*).mp.) or exp Mycoses/pc or (exp Mycoses/ and (prophyla* or prevent*).mp.) or 64 991 (prophylaxis or (prevent* adj2 (fungal or fungus))).ti,ab. 3 Stem Cell Transplantation.mp. or exp Stem Cell Transplantation/ 45 185 4 exp neoplasms/ or (cancer or oncolog*).mp. 2 389 250 5 exp Neutropenia/ or neutropeni*.mp. 28 301 63or4or5 2 426 526 7 1 and 2 and 6 473 8 randomised controlled trial.pt. 314 177 9 controlled clinical trial.pt. 83 186 10 randomised.ab. 220 043 11 drug therapy.fs. 1 486 777 12 randomly.ab. 158 898 13 trial.ab. 227 567 14 groups.ab. 1 054 838 15 8 or 9 or 10 or 11 or 12 or 13 or 14 2 740 074 16 exp animals/ not humans.sh. 3 651 958 17 15 not 16 2 325 347 18 7 and 17 343 Database: EMBASE o1980 to 2011 Week 334 (run on 24 August 2011) 1 fluconazole/ or (fluconazol* or flucolich or arnazole or beagyne or elazor or flucobeta or solacap or diflucan or triflucan or ‘uk 49858’ or uk49858 or 29 035 neofomiral or lavisa or zonal or ‘fluc hexal’ or fluchexal or oxifungol or fungata or loitin or flunazul or zoltrix or Afungil or Alflucoz or Baten or Biocanol or Biozolene or CCRIS 7211 or Canzol or Cryptal or DRG-0005 or Dimycon or Elazor or Mutum or Pritenzol or Syscan or Triconal or Zemyc or Zoltec).mp. 2 (exp Aspergillus/ and (prevent* or prophyla*)).mp. or exp mycosis/pc or (exp mycosis/ and (prevent* or prophyla*)).mp. or ((exp Aspergillus/ or 16 911 exp mycosis/) and (prophylaxis/ or infection prevention/)) 3 stem cell transplantation.mp. or exp stem cell transplantation/ 59 342 4 exp neoplasms/ or (cancer or oncolog*).mp. 2 848 209 5 exp NEUTROPENIA/ or exp FEBRILE NEUTROPENIA/ or neutropenia.mp. 61 135 6 3 or 4 2 876 781 7 1 and 2 and 6 1655 8 randomised controlled trial/ or ct.fs. or random$.mp. or doubl$adj blind$.mp. 996 967 9 7 and 8 554 EBM Reviews—Cochrane Central Register of Controlled Trials, 3rd Quarter 2011 (run on 24 August 2011) 1 fluconazole/ or (fluconazol* or flucolich or arnazole or beagyne or elazor or flucobeta or solacap or diflucan or triflucan or ‘uk 49858’ or uk49858 or 668 neofomiral or lavisa or zonal or ‘fluc hexal’ or fluchexal or oxifungol or fungata or loitin or flunazul or zoltrix or Afungil or Alflucoz or Baten or Biocanol or Biozolene or CCRIS 7211 or Canzol or Cryptal or DRG-0005 or Dimycon or Elazor or Mutum or Pritenzol or Syscan or Triconal or Zemyc or Zoltec).mp. 2 exp Aspergillus/pc or (exp Aspergillus/ and (prophyla* or prevent*).mp.) or exp Mycoses/pc or (exp Mycoses/ and (prophyla* or prevent*).mp.) or 10 404 (prophylaxis or (prevent* adj2 (fungal or fungus))).ti,ab. 3 Stem Cell Transplantation.mp. or exp Stem Cell Transplantation/ or exp Bone Marrow Transplantation/ 2679 4 exp neoplasms/ or (cancer or oncolog*).mp. 56 297 5 neutropenia.mp. or exp Neutropenia/ 3010 63or4or5 58 299 7 1 and 2 and 6 104 Table A2 Stratified analyses by blinding and intention to treat analysis Outcome Trials (patients) RR* (95% CI) P-value P-value for interaction test Blinding Proven or probable IFI 0.52 Blinded 4 (2284) 0.62 (0.42, 0.91) 0.01 Not blinded 14 (2518) 0.71 (0.52, 0.98) 0.27 Invasive aspergillosis 0.60 Blinded 4 (2284) 0.47 (0.23, 0.98) 0.04 Not blinded 11 (22196) 0.59 (0.37, 0.95) 0.03 British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table A2 (Continued ) Outcome Trials (patients) RR* (95% CI) P-value P-value for interaction test IFI-related mortality 0.88 Blinded 3 (1686) 0.68 (0.19, 2.40) 0.54 Not blinded 12 (2586) 0.75 (0.49, 1.15) 0.19 IA-related mortality 0.60 Blinded 2 (1084) 0.84 (0.15, 4.91) 0.85 Not blinded 7 (1530) 0.46 (0.12, 1.77) 0.26 Overall mortality 0.23 Blinded 4 (2284) 0.92 (0.76, 1.11) 0.36 Not blinded 12 (2586) 1.07 (0.90, 1.28) 0.44 ITT analysis Proven or probable IFI 0.83 ITT 4 (1445) 0.74 (0.46, 1.17) 0.2 No ITT 14 (3357) 0.69 (0.44, 1.07) 0.1 Invasive aspergillosis 0.55 ITT 5 (1800) 0.47 (0.27, 0.80) 0.006 No ITT 10 (2703) 0.58 (0.37, 0.91) 0.02 IFI-related mortality 0.60 ITT 5 (1280) 0.60 (0.27, 1.33) 0.21 No ITT 10 (2992) 0.77 (0.49, 1.22) 0.27 IA-related mortality NA ITT 1 (59) Not estimable NA No ITT 8 (2555) 0.62 (0.23, 1.71) 0.36 Overall mortality NA ITT 0 (0) Not estimable NA No ITT 16 (4870) 1.00 (0.88, 1.13) 0.96 Abbreviations: CI¼ confidence interval; IA¼ invasive aspergillosis; IFI¼ invasive fungal infection; ITT¼ intention-to-treat; NA¼ not applicable; RR¼ relative risk. *RRo1 represents an advantage of mould-active coverage compared with fluconazole using a random-effects model. Table A3 Stratified analyses by study population and fluconazole dose Outcome Trials (patients) RR* (95% CI) P-value P-value for interaction test Study population Proven or probable IFI 0.82 HSCT 9 (2415) 0.70 (0.49, 0.99) 0.004 Chemotherapy 4 (1259) 0.59 (0.15, 2.27) 0.45 Invasive aspergillosis 0.73 HSCT 8 (2619) 0.47 (0.29, 0.75) 0.002 Chemotherapy 3 (780) 0.60 (0.16, 2.28) 0.45 IFI-related mortality 0.96 HSCT 8 (2097) 0.81 (0.50, 1.31) 0.39 Chemotherapy 2 (571) 0.78 (0.17, 3.46) 0.74 IA-related mortality 0.23 HSCT 4 (1065) 0.27 (0.03, 2.38) 0.24 Chemotherapy 2 (571) 1.69 (0.21, 13.59) 0.62 Overall Mortality 0.42 HSCT 9 (2697) 1.06 (0.90, 1.25) 0.50 Chemotherapy 2 (571) 0.86 (0.54, 1.38) 0.54 AEs requiring antifungal treatment discontinuation or modification 0.43 HSCT 8 (2111) 2.14 (0.94, 4.87) 0.07 Chemotherapy 3 (780) 1.51 (1.16, 1.98) 0.0003 Fluconazole dose Proven or probable IFI 0.18 Fluconazole X400 mg per day 12 (4044) 0.65 (0.46, 0.93) 0.02 Fluconazole o400 mg per day 6 (758) 1.07 (0.57, 2.00) 0.84 Invasive aspergillosis 0.11 Fluconazole X400 mg per day 11 (3847) 0.49 (0.34, 0.70) 0.0001 Fluconazole o400 mg per day 4 (656) 1.42 (0.41, 4.93) 0.59 IFI-related mortality 0.14 Fluconazole X400 mg per day 9 (3142) 0.57 (0.38, 0.86) 0.007 Fluconazole o400 mg per day 6 (1130) 1.22 (0.49, 3.02) 0.67 IA-related mortality 0.87 Fluconazole X400 mg per day 5 (1748) 0.51 (0.13, 1.95) 0.32 Fluconazole o400 mg per day 4 (866) 0.63 (0.07, 6.09) 0.69 & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies Clinical Studies Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table A3 (Continued ) Outcome Trials (patients) RR* (95% CI) P-value P-value for interaction test Overall mortality 0.87 Fluconazole X400 mg per day 10 (3740) 0.98 (0.85, 1.12) 0.76 Fluconazole o400 mg per day 6 (1130) 1.03 (0.57, 1.88) 0.92 AEs requiring antifungal treatment discontinuation or modification 0.03 Fluconazole X400 mg per day 10 (3213) 1.49 (0.91, 2.43) 0.12 Fluconazole o400 mg per day 6 (1280) 3.19 (2.01, 5.05) 0.0001 Abbreviations: AEs¼ adverse events; CI¼ confidence interval; HSCT¼ haematopoietic stem cell transplantation; IA¼ invasive aspergillosis; IFI¼ invasive fungal infection; ITT¼ intention-to-treat; RR¼ relative risk. *RRo1 represents an advantage of mould-active coverage compared with fluconazole using a random-effects model. Table A4 Meta-regression for primary and secondary outcomes of mould-active vs fluconazole prophylaxis Outcome b s.e. P-value Proven or probable IFI HSCT  0.07 0.35 0.831 Amphotericin 0.86 0.36 0.017 Echinocandin 0.19 0.48 0.698 Other azoles REF REF Fluconazole X400 mg per day  0.52 0.40 0.190 Blinding  0.22 0.26 0.403 ITT  0.24 0.25 0.350 Invasive aspergillosis HSCT  0.35 0.38 0.363 Amphotericin 0.91 0.76 0.233 Echinocandin  0.90 0.91 0.326 Other azoles REF REF Fluconazole X400 mg per day  1.12 0.64 0.080 Blinding  0.10 0.36 0.780 ITT  0.38 0.36 0.286 Adverse events requiring antifungal treatment discontinuation or modification HSCT  0.29 0.52 0.584 Amphotericin 1.06 0.67 0.112 Echinocandin  1.09 0.68 0.112 Other azoles REF REF Fluconazole X400 mg per day  0.83 0.48 0.086 Blinding  1.12 0.30 0.0002 ITT  0.13 0.59 0.833 IFI-related mortality HSCT  0.10 0.48 0.831 Amphotericin 0.37 0.54 0.495 Echinocandin 0.13 0.98 0.896 Other azoles REF REF Fluconazole X400 mg per day  0.70 0.46 0.129 Blinding  0.34 0.41 0.404 ITT  0.42 0.39 0.282 Invasive aspergillosis-related mortality HSCT  0.77 1.35 0.569 Amphotericin 1.17 1.40 0.403 Echinocandin  1.10 1.66 0.506 Other azoles REF REF Fluconazole X400 mg per day  0.50 0.97 0.605 Blinding 0.54 1.00 0.590 ITT 0.35 2.06 0.866 Overall mortality HSCT 0.10 0.20 0.619 Amphotericin 0.14 0.22 0.510 Echinocandin  0.16 0.30 0.591 Other azoles REF REF Fluconazole X400 mg per day  0.17 0.24 0.47 Blinding  0.14 0.15 0.341 ITT  0.05 0.15 0.754 Abbreviations: HSCT¼ haematopoietic stem cell transplantation; IFI¼ invasive fungal infection; ITT¼ intention-to-treat; REF¼ reference category; s.e.¼ standard error. British Journal of Cancer (2012) 106(10), 1626 – 1637 & 2012 Cancer Research UK Fluconazole vs mould-active prophylaxis meta-analysis MC Ethier et al Table A5 Sensitivity analyses for primary and secondary outcomes of mould-active vs fluconazole prophylaxis Sensitivity analysis-studies of itraconazole Analyses for all capsules removed (Annaloro et al, 1995; included studies Huijgens et al, 1999b) Outcome Risk ratio* (95% CI) P-value Risk ratio* (95% CI) P-value Proven or probable IFI 0.71 (0.52, 0.98) 0.03 0.68 (0.49, 0.94) 0.02 Invasive aspergillosis 0.53 (0.37, 0.75) 0.0004 0.50 (0.35, 0.71) 0.0001 Adverse events requiring antifungal treatment discontinuation 1.95 (1.24, 3.07) 0.004 1.95 (1.24, 3.07) 0.004 or modification IFI-related mortality 0.67 (0.47, 0.96) 0.03 0.62 (0.43, 0.90) 0.01 Invasive aspergillosis-related mortality 0.62 (0.23, 1.71) 0.36 0.41 (0.12, 1.39) 0.15 Overall mortality 1.00 (0.88, 1.13) 0.96 0.99 (0.87, 1.13) 0.85 Sensitivity analysis-studies of Itraconazole 200 mg per day removed (Choi et al, 2005; Ito et al, 2007b; Ota et al, 2010) Proven or probable IFI 0.71 (0.52, 0.98) 0.03 0.72 (0.53, 0.99) 0.05 Invasive aspergillosis 0.53 (0.37, 0.75) 0.0004 0.54 (0.38, 0.76) 0.0005 Adverse events requiring antifungal treatment discontinuation 1.95 (1.24, 3.07) 0.004 1.85 (1.13, 3.03) 0.01 or modification IFI-related mortality 0.67 (0.47, 0.96) 0.03 0.66 (0.46, 0.95) 0.02 Invasive aspergillosis-related mortality 0.62 (0.23, 1.71) 0.36 0.62 (0.23, 1.71) 0.36 Overall mortality 1.00 (0.88, 1.13) 0.96 1.00 (0.88, 1.14) 0.98 Abbreviations: CI¼ confidence interval; IFI¼ invasive fungal infection. *RRo1 represents an advantage of mould-active coverage compared with fluconazole using a random- effects model. This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. & 2012 Cancer Research UK British Journal of Cancer (2012) 106(10), 1626 – 1637 Clinical Studies

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