Prophylactic administration of colony-stimulating factors reduces hospital stay and risk of infections in children with acute lymphoblastic leukaemia

The authors evaluated the efficacy of adding colony-stimulating factors (CSF) after chemotherapy in children with acute lymphoblastic leukaemia (ALL) to prevent febrile neutropenia, which is a potentially life-threatening side effect of treatment.

There is a lack of studies to determine the best CSF dose for children and only a small number of RCTs evaluating the role of CSF in children's ALL. The prophylactic administration of CSF reduces hospital stay, and risk of infections. The authors did not find evidence that CSF reduces febrile neutropenia episodes, their duration, or treatment delays in children with ALL undergoing chemotherapy. Follow up was too short to provide useful information on any possible effect on relapse or survival.

Authors' conclusions: 

Children with ALL treated with CSF benefit from shorter hospitalisation and fewer infections. However, there was no evidence of shortened duration of neutropenia nor fewer treatment delays. There was also no useful information about survival.

The role of CSF in the context of febrile neutropenia episodes is still uncertain. Although current data show statistical benefit with CSF use, substantial heterogeneity between included trials does not allow this conclusion.

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Background: 

Acute lymphoblastic leukaemia (ALL) is the most common cancer in childhood and febrile neutropenia is a potentially life-threatening side effect of its treatment. Current treatment consists of supportive care plus antibiotics. Clinical trials have attempted to evaluate the use of colony-stimulating factors (CSF) as additional therapy to prevent febrile neutropenia in children with ALL. Individual trials have not demonstrated significant benefit. Systematic reviews provide the most reliable assessment and the best recommendations for practice.

Objectives: 

To evaluate the safety and effectiveness of the addition of granulocyte colony-stimulating factors (G-CSF) or granulocyte macrophage colony-stimulating factors (GM-CSF) to myelosuppressive chemotherapy in children with ALL in an effort to prevent the development of febrile neutropenia. Evaluation of number of febrile neutropenia episodes, length to neutrophil count recovery, incidence and length of hospitalisation, number of infectious disease episodes, incidence and length of treatment delays, side effects (flu-like syndrome, bone pain and allergic reaction), relapse and overall mortality (death).

Search strategy: 

The search covered the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CANCERLIT, LILACS, and SciElo. We manually searched records of conference proceedings of ASCO and ASH from 1985 to 2003 and used the electronic databases of the ASCO and ASH web sites to search for abstracts from 2003 to September 2008, as well as databases of ongoing trials. We consulted experts and scanned references from the relevant articles.

Selection criteria: 

We looked for randomised controlled trials (RCTs) comparing CSF with placebo or no treatment as primary or secondary prophylaxis to prevent febrile neutropenia in children with ALL.

Data collection and analysis: 

Two authors independently selected and critically appraised studies and extracted relevant data. The end points of interest were:

* Primary end points: number of febrile neutropenia episodes and overall mortality (death)
* Secondary end points: time to neutrophil count recovery, incidence and length of hospitalisation, number of infectious diseases episodes, incidence and length of treatment delays, side effects (flu-like syndrome, bone pain and allergic reaction) and relapse.

We conducted a meta-analysis of these end points and expressed the results as Peto odds ratios. For continuous outcomes we calculated a weighted mean difference and a standardised mean difference. For count data, we conducted a meta-analysis of the logarithms of the rate ratios using generic inverse variance.

Main results: 

We scanned more than 6800 citations and included six studies with a total of 333 participants in the analysis. There were insufficient data to assess the effect on survival. The use of CSF significantly reduced the number of episodes of febrile neutropenia episodes (Rate Ratio = 0.63; 95% confidence interval (CI) 0.46 to 0.85; P = 0.003, with substantial heterogeneity), the length of hospitalisation (weighted mean difference (WMD) = -1.58; 95% CI -3.00 to -0.15; P = 0.03), and number of infectious disease episodes (Rate Ratio = 0.56; 95% CI 0.39 to 0.80; P = 0.002). Despite these results, CSF did not influence the length of episodes of neutropenia (WMD = -1.11; 95% CI -3.55 to 1.32; P = 0.4) or delays in chemotherapy courses (Rate Ratio = 0.75; 95% CI 0.47 to 1.20; P = 0.23) .

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