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Meta-Analysis of Randomized Controlled Trials of Prophylactic Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor After Autologous and Allogeneic Stem Cell Transplantation

Allison Dekker, Sean Bulley, Joseph Beyene, L. Lee Dupuis, John J. Doyle, Lillian Sung

From the Departments of Public Health Sciences, Health Policy Management and Evaluation, and Paediatrics, and Faculty of Pharmacy, University of Toronto; and the Department of Pharmacy, Division of Hematology/Oncology, and Program in Population Health Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada

Address reprint requests to Lillian Sung, MD, PhD, Division of Hematology/Oncology, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8; e-mail: Lillian.sung{at}sickkids.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose: The primary objective of our meta-analysis was to determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) after hematopoietic autologous and allogeneic stem-cell transplantation (SCT) reduced documented infections. Our secondary objectives were to determine whether prophylactic CSFs affected other outcomes including parenteral antibiotic therapy duration, infection-related mortality, graft-versus-host disease (GVHD), or treatment-related mortality.

Methods: We included studies if there was random assignment between CSFs and placebo/no therapy and CSFs were given after SCT and before recovery of neutrophils. From 3,778 reviewed study articles, 34 were included based on predefined inclusion criteria. All analyses were conducted using a random effects model.

Results: CSFs reduced the risk of documented infections (relative risk [RR] 0.87; 95% CI, 0.76 to 1.00; P = .05) and duration of parenteral antibiotics (weighted mean difference, –1.39 days, 95% CI, –2.56 to –0.22; P = .02) but did not reduce infection-related mortality (RR, 0.76; 95% CI, 0.41 to 1.44; P = .4). CSFs did not increase grade 2 to 4 acute GVHD (RR, 1.03; 95% CI, 0.81 to 1.31; P = .8) or treatment-related mortality (RR, 1.00; 95% CI, 0.78 to 1.29; P = .98).

Conclusion: CSFs were associated with a small reduction in the risk of documented infections but did not affect infection or treatment-related mortality.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) are hematopoietic CSFs that decrease the duration and severity of neutropenia in adults and children receiving chemotherapy.^1-5 However, reduction in neutropenia is not meaningful if it is not associated with an improvement in clinically important outcomes, such as the risk of infection, quality of life, costs, or mortality.

In general, clinically important benefits with the prophylactic administration of CSFs have been demonstrated only after administration of more intensive chemotherapy.^3,6,7 Consequently, guidelines published by the American Society of Clinical Oncology suggest that CSFs be used as primary prophylaxis when the expected incidence of chemotherapy-induced febrile neutropenia is greater than 20% to 40%.^8,9 Given the high risk of febrile neutropenia in recipients of stem-cell transplantation (SCT), we postulated that this group of patients might particularly benefit from prophylactic CSF administration.

There have been many randomized trials of prophylactic CSFs in SCT recipients. Most did not show a reduction in clinically important outcomes. However, many studies had limited power to support their conclusion that CSFs were ineffective. In addition, a recent observational study from Europe suggested that G-CSF may have adverse effects.¹⁰ In this retrospective study, G-CSF was associated with increased grade 2 to 4 acute graft-versus-host disease (GVHD; relative risk [RR], 1.33; P = .007), chronic GVHD (RR, 1.29; P = .03), and treatment-related mortality (RR, 1.73; P = .0002) in bone marrow recipients. No such effects were seen among recipients of peripheral blood progenitor cell (PBPC) transplantation.¹⁰

Given the uncertainty in the literature, we hypothesized that synthesis of the data from randomized clinical trials may provide more power and more precise estimates of efficacy of CSFs in SCT. In addition, such an analysis may help to determine whether CSFs are truly associated with an increased risk of GVHD or treatment-related mortality in an unbiased fashion.

Our primary objective was to determine whether prophylactic CSF administration reduced the risk of documented infection in the SCT setting. Our secondary objectives were to determine whether prophylactic CSFs influenced other infection-related outcomes, hematopoietic recovery, blood product utilization, GVHD, duration of hospitalization, treatment-related mortality, and overall survival.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Study Selection
We performed an electronic search of OVID Medline from 1966 to January 12, 2006, and EMBASE from 1980 to January 7, 2006. The search strategy included the medical subject headings and text words "granulocyte colony-stimulating factor," "granulocyte-macrophage colony-stimulating factor," "stem-cell transplant," "bone marrow transplant," and abbreviated, generic, and trade names for all available granulocyte and GM-CSFs, including pegfilgrastim. The set was limited to clinical trials. We also hand searched references and conference proceedings from meetings of the American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and European Group for Blood and Marrow Transplantation in 2004 and 2005. Finally, we contacted the pharmaceutical manufacturers of G-CSF and GM-CSF. The search strategy was purposefully broad to ensure that we did not miss any eligible studies.

We defined inclusion and exclusion criteria a priori. Studies were included if there was randomization between CSFs and placebo or no therapy; CSFs were given after SCT and before recovery of neutrophils; and SCT conditioning regimen and GVHD prophylaxis were not planned to be systematically different between CSF and placebo/no therapy arms. There was no language restriction for inclusion in this meta-analysis.

Two reviewers (A.D. and L.S.) independently evaluated titles and abstracts of publications identified by the search strategy, and any potentially relevant publication was retrieved in full. The reviewers were not blinded to study authors or outcomes. Final inclusion of studies into the meta-analysis was by agreement of both reviewers. Agreement between reviewers on inclusion was evaluated using a statistic. Strength of agreement as evaluated by the statistic was defined as slight (0.00 to 0.20), fair (0.21 to 0.40), moderate (0.41 to 0.60), substantial (0.61 to 0.80), or almost perfect (0.81 to 1.00).¹¹

Data Extraction
The primary outcome measure was the risk of documented infection. We also examined other infection-related outcomes, such as the risk of microbiologically and clinically documented infections, fever duration, parenteral antibiotic therapy duration, antifungal treatment duration, and infection-related mortality. Prophylactic antibacterial and antimycotic administration were not included in the antibiotic and antifungal end points. These outcomes all were defined by individual studies but in principal, documented infection included both microbiologically and clinically documented infections. In addition, we examined outcomes related to hematopoietic recovery including duration of neutropenia (time to an absolute neutrophil count, 0.5 x 10⁹/L and 1.0 x 10⁹/L), duration of thrombocytopenia (time to a platelet count of 20 x 10⁹/L, 50 x 10⁹/L and platelet transfusion independence), number of platelet units transfused, time to RBC transfusion independence, and number of RBC units transfused. Also, we examined outcomes related to GVHD in allogeneic trials including the risk of grade 2 to 4 acute GVHD, grade 3 to 4 acute GVHD, and chronic GVHD. Finally, we examined duration of initial hospitalization after SCT, treatment-related mortality, and overall survival. Costs and quality of life also were examined. Authors were contacted to obtain information not available in publications. Data extraction was performed by two reviewers (A.D. and L.S.).

Assessment of Study Quality
Study quality was examined using an 11-point scale that examines threats to validity of randomized controlled trials.¹² This scale includes elements such as adequacy of method of randomization, concealment of treatment allocation, blinding, and analysis by intention-to-treat. Agreement in study quality determination as extracted by two reviewers was rated using the intraclass correlation coefficient.

Statistical Methods
This meta-analysis combined data at the study level and not at the individual patient level. Because of differences in how summary statistics for continuous outcomes were presented, we made the following assumptions to facilitate data synthesis: the mean could be approximated by the median, the range contained six standard deviations, the 95% CI contained four standard errors and the interquartile range contained 1.35 standard deviations.

Some trials included more than one CSF intervention group (for example, CSF initiation on days 0 or 7 after SCT). We performed the baseline analysis with the group expected to have the greatest degree of benefit if a benefit existed (ie, day 0 in this example). However, we also performed a sensitivity analysis to the alternate extreme (ie, day 7 in this example) to determine whether this choice affected inferences.

Categoric outcome data were synthesized using RR as the effect measure; RR less than 1 suggests that CSFs are associated with a reduction in that outcome. For the primary outcome, we also examined the risk difference and number needed to treat to prevent one event. Continuous outcome variables were expressed as the weighted mean difference (WMD), which represents the overall difference between CSF and placebo or no therapy strategies. For example, the WMD for fever duration is the overall difference in days of fever between CSF and placebo/no therapy, with negative numbers indicating that duration was shorter with CSFs. Effect sizes were weighted by the inverse variance.

Because we anticipated heterogeneity between studies, a random effects model¹³ was used for all analyses. We also explored the potential sources of heterogeneity with subgroup analyses by CSF type (G-CSF v GM-CSF), SCT type (autologous v allogeneic), stem cell source (PBPC v bone marrow), and adult versus pediatric recipient. In addition, we examined the effect of CSF type and stem cell source within allogeneic and autologous recipients separately, and year of publication ( 1995 v > 1995). In the stratified analyses, only outcomes with at least two studies per group were examined. If a study included both subgroups (for example, autologous and allogeneic), this study was excluded from the relevant stratified analysis (SCT type in this example), but could be included in other stratified analyses if appropriate. The results of the stratified analyses must be interpreted cautiously given the number of analyses performed, and the small number of studies in some strata. In general, we searched for substantially different effects between subgroups as a suggestion of heterogeneity rather than relying on P values.

Publication bias, which occurs when small studies are published only if the results are positive, was examined using a funnel plot. This plot is a graph with the effect size (RR or WMD) on the x-axis and the inverse of variance of the effect on the y-axis. Asymmetry, without studies in the bottom left or right corner, depending on the effect measure, suggests publication bias.¹⁴ In the event of possible publication bias, the trim and fill technique was used to determine the impact of such bias.¹⁴ With this technique, outlying studies are deleted and hypothetical negative studies with equal weight are created to determine the robustness of the conclusions of the analysis.

This meta-analysis was performed using Review manager (RevMan, version 4.2, The Cochrane Collaboration, Oxford, England). For all borderline 95% CIs, we also performed nonparametric bootstrap sampling with replacement and generated bias-corrected adjusted bootstrap percentile intervals.^15,16

	RESULTS

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A total of 3,778 titles and abstracts were reviewed, and 187 full articles were retrieved. Of these, 33 satisfied predefined inclusion criteria and were included in the final meta-analysis.^4,5,17-47 Reasons for excluding 154 articles were: absence of placebo/no treatment arm (n = 53); allocation not randomized (n = 64); intervention not administered after SCT and before recovery of neutrophils (n = 8); duplicate publication (n = 24); administration of CSFs other than G-CSF or GM-CSF (n = 4); and no data (n = 1). In addition, one eligible trial was identified from the review of abstracts,⁴⁸ resulting in a total of 34 included studies. The reviewers had almost perfect agreement on articles for inclusion, with a statistic of 0.95 (95% CI 0.89 to 0.99).

Demographics of the 34 included studies are illustrated in Table 1. The 34 studies included 2,669 participants, 1,348 randomly assigned to CSF and 1,321 randomly assigned to control arms. Of the 34 studies, 20 (59%) indicated pharmaceutical company support. In the assessment of study quality using the 11-point scale, there was substantial inter-rater agreement, with an intraclass correlation coefficient of 0.71 (95% CI 0.50 to 0.85). The median study quality score was 7 (range, 3 to 10).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Forest plot of the risk of documented infections with colony-stimulating factors. Squares to the left of the vertical line indicate the intervention reduces documented infections. Horizontal lines through the squares represent 95% CIs. The size of the squares reflects each study's relative weight and the diamond represents the aggregate relative risk (RR) and 95% CI.

In terms of hematopoietic recovery, Table 2 illustrates that CSFs did not increase the time to reach a platelet count of 20 x 10⁹/L but did increase the time to reach a platelet count of 50 x 10⁹/L (WMD, 2.31; P = .02). This delay did not translate into increased platelet utilization. Table 2 also shows that CSFs were not associated with differences in the risk of acute or chronic GVHD, treatment-related mortality, or overall survival. CSFs were associated with a three day reduction in hospitalization duration (Table 2).

Tables 3 to 6 and online only Appendix Tables A1 to A4 illustrate the stratified analyses. Not all outcomes are represented because some outcomes had less than two studies in a subgroup. The baseline risk of documented infection was 70% in the allogeneic and 63% in the autologous groups. In determining whether the risk of infection varied among subgroups, we not only looked at a difference in CSF effect between these subgroups, but, also, whether this difference was consistent between documented and microbiologically documented infections. For almost all outcomes other than those discussed herein, the stratified analyses did not demonstrate qualitatively different results.

Tables 3 illustrates that two outcomes were dissimilar when G-CSF and GM-CSF were examined separately. While G-CSF was associated with reductions in duration of fever and duration of parenteral antibiotic therapy, GM-CSF was associated with a statistically significant increase in both outcomes. In addition, another possible dissimilar result was the effect of CSFs on infection-related mortality in autologous (RR, 1.09) and allogeneic SCT (RR, 0.37; Table 4).

There were four studies in which there were multiple CSF groups (for example, different doses or days of CSF initiation) and thus data from only one group per study was presented in the baseline analysis.^27,33,39,42 When we repeated data synthesis including data from the other extreme group of each of these studies, results were qualitatively unchanged (data not shown). When the analysis of documented infections was stratified by unblinded versus blinded (placebo controlled) studies, unblinded studies did not show a stronger reduction in documented infections, with RR 0.96 for unblinded studies (95% CI, 0.82 to 1.14; P = .6) and RR 0.81 for blinded studies (95% CI, 0.65 to 1.02; P = .08).

Publication bias was suggested in one outcome, the time to reach an absolute neutrophil count of 1.0 x 10⁹/L. Repeated analysis with the trim and fill method did not substantively change the estimate of treatment effect (data not shown).

Costs were examined within the original publication of seven studies^{5,23,31,36,38,41,46} and presented in separate publications in four others.^49-52 Ten studies are illustrated in Table 7 as one study did not specify costs other than to state that costs were not significantly different between the CSF versus no therapy strategy.⁴⁶ Because of considerable heterogeneity in how costs were obtained and modeled, we did not combine the data quantitatively. When we qualitatively examined the direction of costs, seven studies found that CSFs were associated with cost savings while three found that CSFs were associated with cost liability (Table 7). However, two of the studies that demonstrated cost savings did not include the CSF cost in their estimates. Quality of life was not reported in any of the 34 included studies.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

Our results are consistent with most meta-analyses of prophylactic CSF administration in which CSFs reduce infection but do not decrease infection-related mortality. For example, Lyman et al⁵³ concluded that G-CSF reduced documented infections, (odds ratio, 0.51; P = .001) but did not reduce infection-related mortality (odds ratio, 0.60; P = .2). Similarly, Bohlius et al^54,55 found that CSFs reduced microbiologically documented infections (RR, 0.74; 95% CI, 0.64 to 0.85) but did not affect infection-related mortality (RR, 2.07; 95%, 0.81 to 5.34). A pediatric systematic review also concluded that CSFs reduced documented infections (rate ratio, 0.78; P = .02) but did not affect infection-related mortality (rate ratio, 1.02; P = .97).⁵⁶

We also demonstrated that CSFs do not increase acute or chronic GVHD, either among the entire group or bone marrow recipients. Furthermore, CSFs were not associated with higher treatment-related mortality or inferior overall survival among any allogeneic SCT subgroup. In fact, CSFs may have been associated with a greater reduction in infection-related mortality in allogeneic compared with autologous recipients. Our GVHD findings are concordant with another systematic review that concluded that CSFs were not associated with increased acute or chronic GVHD.⁵⁷ However, several retrospective studies have suggested increased acute GVHD or treatment-related mortality in CSFs-treated allogeneic recipients.^10,58,59 The explanation for differences between our meta-analysis based on randomized trials and retrospective studies is likely related to unmeasured confounders and sources of bias that may influence nonrandomized studies. Consequently, our findings are important as we present estimates of the effect of CSFs on GVHD and treatment-related mortality that should be unbiased.

In general, the stratified analyses failed to demonstrate differences apart from fewer days of fever and shorter duration of parenteral antibiotics in the G-CSF compared with the GM-CSF group, and possibly lower infection-related mortality in allogeneic compared with autologous recipients. However, the small number of studies in some subgroups may have limited our ability to detect differences in these subgroups.

Our study was limited because detailed microbiological data were rarely presented, and thus, further exploration by type of infection (for example, bacterial, viral, and fungal) was not possible. Second, we restricted this systematic review to randomized trials in order to minimize bias and consequently did not use data available in single-arm trials.

On balance, whether or not CSFs should be routinely administered after SCT is not clear. Proponents of CSFs may argue that this meta-analysis has demonstrated that CSFs are associated with a clinical benefit (8% absolute decrease in the risk of documented infections) and that CSFs are not associated with negative effects, such as GVHD or treatment-related mortality. In addition, the majority of cost analyses demonstrated that prophylactic CSF administration had either no significant impact on the financial cost of SCT or resulted in cost savings. However, others may argue that the clinical benefits of routine CSF administration after SCT are small and do not sufficiently influence transplant outcomes to warrant routine administration, particularly given the inconsistency in the direction of the reported cost benefit.

In summary, we have demonstrated that CSFs are associated with a small decrease in the risk of documented infections in the SCT setting. CSFs did not increase GVHD or treatment-related mortality among allogeneic SCT recipients.

	Appendix

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

	Author Contributions

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Allison Dekker, Sean Bulley, Joseph Beyene, L. Lee Dupuis, John J. Doyle, Lillian Sung Collection and assembly of data: Allison Dekker, Lillian Sung Data analysis and interpretation: Joseph Beyene, Lillian Sung Manuscript writing: Allison Dekker, Joseph Beyene, L. Lee Dupuis, John J. Doyle, Lillian Sung Final approval of manuscript: Allison Dekker, Sean Bulley, Joseph Beyene, L. Lee Dupuis, John J. Doyle, Lillian Sung

 

	ACKNOWLEDGMENTS

 
We thank Elizabeth Uleryk for her expertise and assistance with the literature search and Sinyoung Park for administrative assistance.

	NOTES

 
Supported in part by a Career Development Award by the Canadian Child Health Clinician Scientist Program (L.S.), a Canadian Institutes of Health Research strategic training program.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 13, 2006; accepted September 6, 2006.

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