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Prophylactic Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Decrease Febrile Neutropenia After Chemotherapy in Children With Cancer: A Meta-Analysis of Randomized Controlled Trials

From the Departments of Pediatrics, Health Policy Management and Evaluation, and Public Health Sciences, University of Toronto; Division of Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada; National Cancer Institute, Pediatric Oncology Branch, Rockville, MD; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; and Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX

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

	ABSTRACT

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

 
PURPOSE: To determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) used in children with cancer reduce the rate of febrile neutropenia, hospitalization duration, documented infection rate, parenteral antibiotic duration, amphotericin B use, or infection-related mortality.

METHODS: We included studies in this meta-analysis if their populations consisted of children, if there was randomization between CSFs and placebo or no therapy, if CSFs were administered prophylactically (before neutropenia or febrile neutropenia), and if chemotherapy treatments preceding CSFs and placebo or no therapy were identical. From 971 reviewed study articles, 16 were included.

RESULTS: The mean rate of febrile neutropenia in the control arms was 57% (range, 39% to 100%). Using a random effects model, CSFs were associated with a reduction in febrile neutropenia, with a rate ratio of 0.80 (95% CI, 0.67 to 0.95; P = .01), and a decrease in hospitalization length, with a weighted mean difference of –1.9 days (95% CI, –2.7 to –1.1 days; P < .00001). CSF use was also associated with reduction in documented infections (rate ratio, 0.78; 95% CI, 0.62 to 0.97; P = .02) and reduction in amphotericin B use (rate ratio, 0.50; 95% CI, 0.28 to 0.87; P = .02). There was no difference in duration of parenteral antibiotic therapy (weighted mean difference, –4.3; 95% CI, –10.6 to 2.0 days; P = .2) or infection-related mortality (rate ratio, 1.02; 95% CI, 0.34 to 3.06; P = .97).

CONCLUSION: CSFs were associated with a 20% reduction in febrile neutropenia and shorter duration of hospitalization; however, CSFs did not reduce infection-related mortality.

	INTRODUCTION

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Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are hematopoietic colony-stimulating factors (CSFs) that decrease the duration and severity of neutropenia in adults and children who receive chemotherapy for cancer.^1,2 However, reduction in neutropenia is not meaningful if it is not associated with an improvement in clinically important outcomes such as febrile neutropenia, documented infection, quality of life (QoL), mortality, and/or costs. Guidelines published by the American Society of Clinical Oncology (ASCO) suggest that CSFs be used as primary prophylaxis (before onset of neutropenia or febrile neutropenia) when the expected incidence of febrile neutropenia is 40% or more.^2-4 This recommendation is based on reduced febrile neutropenia in adult clinical trials, when the rate of febrile neutropenia in the control arm was at least that much.^5-7

CSFs have received less attention in children than adults, and therefore, their effect in pediatric cancer is less clear.¹ Children with cancer differ from adults with cancer; chemotherapy often is more intensive and more likely to result in severe myelosuppression.⁸ Episodes of febrile neutropenia also are associated with better response to empiric therapy and lower mortality rates in children compared with adults.⁹ Because there is little evidence from randomized controlled trials (RCTs) on the efficacy of CSFs in pediatric patients, the recent ASCO guidelines suggest that recommendations for adults be applied to children,^2-4 and that further research into CSFs in the pediatric setting is warranted.²

Of the few studies that assessed CSFs for primary prophylaxis in children with cancer, most did not show reduced febrile neutropenia rates.^10-16 However, many studies had limited power to conclude that CSFs were ineffective. Consequently, we hypothesized that synthesis of the data may provide more power and more precise estimates of efficacy of CSFs in children with cancer. Although these studies used different CSFs and doses, we believed that the data were combinable because G-CSF and GM-CSF are generally considered interchangeable in terms of efficacy in many clinical situations,¹ and because in other contexts, differences in outcome such as duration of neutropenia and rate of infectious complications have not been shown with different CSF formulations^17-21 or dosages.²²

Our primary objective was to determine whether prophylactic CSFs are associated with a reduction in the rate of febrile neutropenia in children who receive chemotherapy for cancer. Our secondary objectives were to determine whether prophylactic CSFs are associated with reductions in hospitalization duration, documented infection, parenteral antibiotics duration, amphotericin B use, length of chemotherapy delay, or infection-related mortality.

	METHODS

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Study Selection
We performed an electronic search of OVID MEDLINE from 1966 to July 2003, and EMBASE from 1980 to July 2003. The search strategy included the Medical Subject Headings and text words "granulocyte-colony-stimulating factor," "granulocyte-macrophage colony-stimulating factor," and "neoplasms," and the set was limited to RCTs that included children 18 years old. We also hand-searched relevant references and conference proceedings from meetings of the American Society of Hematology, ASCO, the Society Internationale Oncologie Pediatric, and the American Society of Pediatric Hematology/Oncology from January 2001 to January 2003. Finally, we contacted the pharmaceutical manufacturers of G-CSF and GM-CSF.

We defined a priori inclusion and exclusion criteria. Studies were included if (1) the population consisted of children (age defined by the individual study) or if data were extractable for those 18 years old in studies that included adults and children; (2) there was randomization between CSFs and placebo or no therapy; (3) CSFs were given after initiation of chemotherapy, prophylactically, before development of neutropenia or febrile neutropenia; and (4) identical chemotherapy immediately preceded CSF and placebo administration or no therapy. For describing reasons for exclusion, we used a hierarchical system in which reasons for exclusion were ranked in the following order: study population consisted of adults, allocation was not randomized, different chemotherapy regimens preceded CSFs and placebo or no therapy, absence of a placebo or no therapy arm, and duplicate publication.

Two reviewers (L.S. and P.N.) 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. Disagreements were resolved by consensus and when there was no consensus, a third investigator arbitrated. 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).²³

Data Extraction
Outcome measures were occurrence of febrile neutropenia, neutropenia duration, hospitalization duration, rate of documented infections, parenteral antibiotic therapy duration, amphotericin B use, chemotherapy delay length, and infection-related mortality. Cost-effectiveness and QoL were also examined. Authors were contacted to obtain information not available in publications. Data extraction was also performed by two reviewers (L.S. and P.N.).

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

Because several of the trials applied the assigned intervention after a single random assignment to multiple cycles of chemotherapy, there was added complexity to the analysis. For studies in which data were presented separately for different cycles (eg, presenting the results after acute lymphoblastic leukemia [ALL] induction and consolidation therapy separately), only the data from the first cycle were included. For studies in which data from all cycles were presented in an aggregate manner, events were assumed to follow a Poisson distribution, and were presented per cycle. The outcome then was expressed as the natural logarithm of the rate ratio with the variance of the rate ratio determined using the Delta method.²⁴ Continuous outcomes were presented as average effect per cycle. Therefore, in general, each study contributed one effect estimate for each outcome with available data.

Synthesized continuous data 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 hospitalization duration is the overall difference in days of hospitalization between CSF and placebo or no therapy strategies, with negative numbers indicating that duration was shorter with CSFs. Categorical data were expressed as rate ratios, which can be considered analogous to a relative risk. A rate ratio less than 1 with a 95% CI that does not include 1 suggests that CSFs are associated with a reduction in outcome. When there were outcomes with no events, 0.5 was added to each cell to allow for calculable values. Effect sizes were weighted by the inverse variance.

Because we anticipated heterogeneity between studies, a random effects model²⁵ was used for all analyses. We also explored the potential causes of heterogeneity by using subgroup analyses for CSF type (G-CSF v GM-CSF) as well as study population (acute leukemia and non-Hodgkin's lymphoma [NHL] v solid tumors). In the stratified analyses, only outcomes with at least two studies per group were examined.

Publication bias, which occurs when small studies are published only if the results are positive, was examined using a funnel plot, which is a graph with the effect size (WMD or rate ratio) 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.²⁶ In the event of possible publication bias, the "trim and fill" technique was used to determine the impact of such bias.²⁶ 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).

Assessment of Study Quality
Study quality was examined using a published 11-point scale that examines threats to validity of RCTs.²⁷ 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 (L.S. and P.N.) was rated using the quadratic weighted statistic.

	RESULTS

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A total of 971 titles and abstracts were reviewed, and 53 full articles were retrieved. Of these, 16 satisfied criteria and were included in the final meta-analysis.^10-16,28-36 The reasons for excluding 37 articles were: adult subjects or data not extractable for children (34 articles), nonrandomized design (one article), and secondary publication (two articles). The reviewers had almost perfect agreement on articles for inclusion, with a of 0.92 (95% CI, 0.80 to 0.99).

Demographics of the 16 included studies are presented in Table 1. In total, the 16 studies included 1,183 children, 592 of whom were randomly assigned to CSF, and 591, to control arms. One study reported two effects for the reported outcomes because results were stratified by two different chemotherapy regimens.¹² Five of the studies evaluated GM-CSF, while 11 evaluated G-CSF. The primary diagnosis was acute leukemia or NHL in 11 studies, solid tumor in four studies, and both acute leukemia and solid tumor in one study. There were 10 studies that included children with ALL or NHL; CSFs were administered after induction chemotherapy in three studies,^14,15,30 after intensification or consolidation chemotherapy in five studies,^{10,11,32,33,35} and after induction and consolidation chemotherapy in two studies.^12,31 Of the 16 included studies, pharmaceutical company support was reported in four.^10,11,31,34

When the data from all 16 studies were synthesized, the mean rate of febrile neutropenia in the control arms was 57% (range, 39% to 100%). Table 2 and Figure 1 illustrate that CSFs reduced the rate of febrile neutropenia with a rate ratio of 0.80 (95% CI, 0.67 to 0.95; P = .01). Table 2 also illustrates that intervention decreased neutropenia duration by approximately 4 days, and reduced hospitalization duration by approximately 2 days. There also was a reduction in documented infection and amphotericin B use in subjects who received CSFs (Table 2). There was no difference in infection-related mortality, with a rate ratio of 1.02 (95% CI, 0.34 to 3.06; P = .97).

View larger version (20K): [in this window] [in a new window]   Fig 1. Forest plot of the rate of febrile neutropenia with colony-stimulating factors. Squares () to the left of the vertical line indicate that the intervention reduces febrile neutropenia. 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 rate ratio and 95% CI.

Publication bias was suggested in one outcome—the rate of febrile neutropenia. For this analysis, one study was an asymmetric outlier.³⁶ When the analysis was repeated with exclusion or trimming of that study in the left lower corner of the funnel plot, the synthesized random effect rate ratio for the remaining studies was 0.82 (95% CI, 0.70 to 0.96). We then added a hypothetical study with equal weight but negative effect; the resultant synthesized rate ratio was 0.81 (95% CI, 0.66 to 0.99). These findings suggest that possible publication bias would have minimal impact on this analysis.

Cost-effectiveness was examined within the original publication of three studies^15,32,36 and presented in separate publications in three others.^37-39 Because of considerable heterogeneity in how costs were obtained and modeled, we did not combine the data quantitatively. Within individual analyses, significant differences in cost were not found. When we qualitatively examined the direction of costs, three studies found that treatment with CSFs was associated with higher costs,^32,37,39 whereas three others found that CSFs were associated with lower costs.^15,36,38 QoL was not reported in any of the 16 included studies.

	DISCUSSION

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

 
We found that prophylactic CSFs in children with cancer reduced the rate of febrile neutropenia by 20% and decreased hospitalization duration by approximately 2 days. Prophylactic CSFs also reduced the documented infection rate by 22% and amphotericin B use by 50%. However, CSFs were not associated with a reduction in infection-related mortality. The subgroup analysis of CSFs in children with acute leukemia/NHL was virtually identical to the main analysis, showing that CSFs reduced febrile neutropenia, decreased hospitalization duration, and reduced the documented infection rate, but did not affect infection-related mortality in this population. Although there have been several narrative reviews of prophylactic CSFs in children with cancer,^1,40,41 our study is important because it is the first study, to our knowledge, to quantitatively synthesize the evidence in this setting.

Because all of the included studies in this meta-analysis had rates of febrile neutropenia 39% in their control arms, our findings are only generalizable to treatment regimens that are similarly myelosuppressive. Our findings therefore concur with ASCO guidelines that recommend CSFs for children whose chemotherapy is anticipated to result in rates of febrile neutropenia 40%. Our results also are consistent with the findings of Lyman et al, who performed a meta-analysis of prophylactic G-CSF in adults with solid tumors or malignant lymphomas.⁴² Their analysis concluded that G-CSF was associated with reduced febrile neutropenia and documented infection but had no effect on infection-related mortality. Our findings are also consistent with a meta-analysis of prophylactic G-CSF or GM-CSF in adults with malignant lymphoma that concluded that CSFs reduced the rate of febrile neutropenia and infection, but did not affect the rate of infection-related mortality.⁴³

In some of the included studies, the allocated therapy was administered during more than one phase or cycle of chemotherapy (such as induction and consolidation for ALL), and investigators reported their results for the different phases separately. For these studies, we included only the first studied cycle of chemotherapy because the effect in different cycles within individuals is not independent, and the variance of the combined effect could not be estimated unless the degree of correlation was known. However, this approach meant that in two studies of ALL,^12,31 only the results of CSFs after induction were included, and the results after consolidation were not analyzed. This approach may have underestimated our estimates of the efficacy of CSFs, as Laver et al³¹ found that CSFs reduced neutropenia duration only during the consolidation phase and not during induction. However, our results were similar when data from only the second cycle were included.

We performed two stratified analyses because we anticipated some heterogeneity in results. In general, similar effects were seen with G-CSF versus GM-CSF; it is unlikely that the qualitative difference in infection-related mortality is meaningful given the wide CIs around the estimates. The results in those with acute leukemia/NHL and solid tumors also were very similar, supporting the inclusion of both groups of diagnoses in this meta-analysis.

Although we showed that CSFs reduce febrile neutropenia, hospitalization duration, documented infections, and amphotericin B use, some may argue that it is unclear whether on-balance CSFs should be advocated for patients. An intervention is of clinical value if it improves length of life, QoL, and/or cost. Given the rarity of mortality, it is unlikely that a significant benefit can be shown by RCTs. It also is unlikely that the decision to use CSFs will be based solely on projected costs, since an equal number of studies demonstrated cost savings and cost liability. However, prospective acquisition of costs would help better define the actual costs associated with each strategy. Therefore, an important determinant of the decision to use CSFs may be QoL. The ASCO guideline presumed that the rate of febrile neutropenia, antibiotic therapy requirement, and need for hospitalization were indirect indicators of QoL.² If we make the same argument, then we also could advocate CSF use in pediatric cancer. However, explicit measurement of QoL in CSF studies would better define potential differences in QoL between intervention and no-treatment strategies. Without explicit QoL measurement, we cannot determine the effect of CSF administration (such as the requirement for injections and increased laboratory monitoring) on children and their families, and whether the gains associated with reduced febrile neutropenia and hospitalization duration are offset by these factors. Furthermore, all the studies we reviewed admitted children with febrile neutropenia to the hospital for parenteral antibiotic therapy. As other management strategies for low-risk febrile neutropenic patients evolve, such as home oral or home parenteral antibiotic therapy,⁴⁴ any difference in QoL between strategies might diminish even further. We therefore suggest that prospective measurement of QoL is important in future studies of CSF prophylaxis in children with cancer. In conjunction with measurement of QoL and costs, we suggest that future studies be designed to identify the group of children who might benefit most from CSF therapy.

Our findings are limited by the small sample sizes of many of the trials; however, an assessment of the effect of potential publication bias suggested that omission of small negative studies would not have affected the conclusions of this meta-analysis. Future studies of CSFs in children with cancer should include explicit measurement of QoL, careful acquisition of costs, and identification of children at particularly high risk who might benefit most from CSF therapy.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by fellowships from the Canadian Institutes of Health Research and the Hospital for Sick Children Clinician Scientist Program (L.S.).

This project was a Children's Oncology Group Cancer Control initiative.

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

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Submitted September 22, 2003; accepted May 11, 2004.

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