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Meta-analysis: Effect of Prophylactic Hematopoietic Colony-Stimulating Factors on Mortality and Outcomes of Infection

Lillian Sung, MD, PhD; Paul C. Nathan, MD, MSc; Shabbir M.H. Alibhai, MD, MSc; George A. Tomlinson, PhD; and Joseph Beyene, PhD
[+] Article and Author Information

From the University of Toronto, The Hospital for Sick Children, and University Health Network, Toronto, Ontario, Canada.


Grant Support: In part by a career development award with the Canadian Child Health Clinician Scientist Training Program, a strategic program with the Canadian Institutes of Health Research (Dr. Sung).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Lillian Sung, MD, PhD, Division of Haematology/Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; e-mail, lillian.sung@sickkids.ca.

Current Author Addresses: Drs. Sung and Nathan: Division of Haematology/Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.

Dr. Alibhai: Toronto General Hospital, Room EN 14-214, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.

Dr. Tomlinson: Toronto General Hospital, Eaton Building East, Room 238, 13th Floor, 200 Elizabeth Street, Ontario M5G 2C4, Canada.

Dr. Beyene: Child Health Evaluative Sciences, Research Institute of The Hospital for Sick Children, Room 1206, 123 Edward Street, Toronto, Ontario M5G 1E2, Canada.


Ann Intern Med. 2007;147(6):400-411. doi:10.7326/0003-4819-147-6-200709180-00010
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Background: Benefits of prophylactic hematopoietic colony-stimulating factors (CSFs) in adults and children receiving cancer chemotherapy or undergoing stem-cell transplantation (SCT) are unclear.

Purpose: To determine whether prophylactic CSFs decrease mortality, infections, and febrile neutropenia more than does placebo or no therapy in patients with cancer and in patients undergoing SCT.

Data Sources: Electronic searches of Ovid MEDLINE and EMBASE from inception until April 2007 and of the Cochrane Central Register of Controlled Trials until the second quarter of 2006.

Study Selection: We selected 148 trials that were reported in any language that randomly assigned patients to CSFs or to either placebo or no therapy. Prophylactic CSFs were given concurrently with or after initiation of chemotherapy.

Data Extraction: Two reviewers independently extracted data onto standardized forms.

Data Synthesis: Short-term all-cause mortality appeared to be similar between the prophylactic CSF and the control groups (7.6% vs. 8.0%; relative risk, 0.95 [95% CI, 0.84 to 1.08]; absolute risk reduction, 0.4% [CI, −0.5% to 1.4%]). Risks for infection-related death with CSFs and placebo or no therapy were 3.1% and 3.8%, respectively (relative risk, 0.82 [CI, 0.66 to 1.02]; absolute risk reduction, 0.8% [CI, 0.0% to 1.5%]). Use of CSFs reduced the following more than did placebo or no therapy: documented infections (median rate, 38.9% vs. 43.1%; rate ratio, 0.85 [CI, 0.79 to 0.92]), microbiologically documented infections (median rate, 23.5% vs. 28.6%; rate ratio, 0.86 [CI, 0.77 to 0.96]), and episodes of febrile neutropenia (median rate, 25.3% vs. 44.2%; rate ratio, 0.71 [CI, 0.63 to 0.80]).

Limitations: Trial designs, including assessments of infections, and participants were heterogeneous. Estimates of mortality effects were imprecise.

Conclusions: Prophylactic CSFs may have little or no effect on mortality but do decrease rates of infection in patients receiving cancer chemotherapy or those undergoing SCT.

Figures

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Figure 1.
Flow diagram of trial identification and selection.

CSF = colony-stimulating factor; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; SCT = stem-cell transplantation.

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Figure 2.
Forest plot of all-cause mortality associated with colony-stimulating factors.RR

Squares represent the point estimate of the outcome of each included study. Squares to the left of the vertical line indicate that colony-stimulating factor reduces mortality compared with placebo or no treatment. Horizontal lines around the squares represent 95% CIs. The size of the squares reflects each study's relative weight, and the diamond represents the aggregate risk ratio ( ) and 95% CI.

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Figure 3.
Primary and secondary outcomes associated with colony-stimulating factors, by patient characteristics. Top.Bottom.P

Stratified analyses by age of patient population. Stratified analyses by underlying diagnosis of patient population. Squares represent the point estimate of the outcome for that stratum. Squares to the left of the vertical line indicate that colony-stimulating factor administration reduces that outcome. Horizontal lines around the squares represent 95% CIs. The effect measures are relative risks for all-cause mortality and infection-related mortality and rate ratios for infections and febrile neutropenia. The values for interaction refer to an interaction between colony-stimulating factor effect and strata and were derived from meta-regression. All analyses used a random-effects model. SCT = stem-cell transplantation; ST = solid tumor.

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Appendix Figure 1. Squares represent the point estimate of the outcome for that stratum. Squares to the left of the vertical line indicate that the colony-stimulating factor intervention reduces that outcome. Horizontal lines around the squares represent 95% CIs. The effect measures are relative risks for all-cause mortality and infection-related mortality and rate ratios for infections and febrile neutropenia. The values for interaction refer to an interaction between colony-stimulating factor effect and strata and were derived from meta-regression. All analyses used a random-effects model.
Stratified analyses by studies that mandated antibacterial prophylaxis in the study design.P
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Appendix Figure 2. Squares represent the point estimate of the outcome of each included study. Squares to the left of the vertical line indicate that the colony-stimulating factor intervention reduces mortality compared with placebo or no treatment. Horizontal lines around the squares represent 95% CIs. The size of the squares reflects each study's relative weight, and the diamond represents the aggregate risk ratios ( ) and 95% CIs overall and for each stratum.
Forest plot of all-cause mortality associated with colony-stimulating factors, by age group.RRs
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Appendix Figure 3. Squares represent the point estimate of the outcome of each included study. Squares to the left of the vertical line indicate that the colony-stimulating factor intervention reduces mortality compared with placebo or no treatment. Horizontal lines around the squares represent 95% CIs. The size of the squares reflects each study's relative weight, and the diamond represents the aggregate risk ratios ( ) and 95% CIs overall and for each stratum.
Forest plot of all-cause mortality associated with colony-stimulating factors, by diagnosis.RRs
Grahic Jump Location
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Appendix Figure 4. Squares represent the point estimate of the outcome of each included study. Squares to the left of the vertical line indicate that the colony-stimulating factor intervention reduces mortality compared with placebo or no treatment. Horizontal lines around the squares represent 95% CIs. The size of the squares reflects each study's relative weight, and the diamond represents the aggregate risk ratios ( ) and 95% CIs overall and for each stratum.
Forest plot of all-cause mortality associated with colony-stimulating factors, by studies that mandated antibacterial prophylaxis.RRs
Grahic Jump Location
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Appendix Figure 5. Squares represent the point estimate of the outcome of each included study. Squares to the left of the vertical line indicate that the colony-stimulating factor intervention reduces mortality compared with placebo or no treatment. Horizontal lines around the squares represent 95% CIs. The size of the squares reflects each study's relative weight, and the diamond represents the aggregate risk ratios ( ) and 95% CIs overall and for each stratum.
Forest plot of infection-related mortality associated with colony-stimulating factors, by age group.RRs
Grahic Jump Location
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Appendix Figure 6. Squares represent the point estimate of the outcome of each included study. Squares to the left of the vertical line indicate that the colony-stimulating factor intervention reduces mortality compared with placebo or no treatment. Horizontal lines around the squares represent 95% CIs. The size of the squares reflects each study's relative weight, and the diamond represents the aggregate risk ratios ( ) and 95% CIs overall and for each stratum.
Forest plot of infection-related mortality associated with colony-stimulating factors, by diagnosis.RRs
Grahic Jump Location
Grahic Jump Location
Appendix Figure 7. Squares represent the point estimate of the outcome of each included study. Squares to the left of the vertical line indicate that the colony-stimulating factor intervention reduces mortality compared with placebo or no treatment. Horizontal lines around the squares represent 95% CIs. The size of the squares reflects each study's relative weight, and the diamond represents the aggregate risk ratios ( ) and 95% CIs overall and for each stratum.
Forest plot of infection-related mortality associated with colony-stimulating factors, by studies that mandated antibacterial prophylaxis.RRs
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