Very early discharge versus early discharge versus non-early discharge in children with cancer and fever during neutropenia

Review question
In this review of the literature we aimed to determine whether early discharge (less than five days, on average) from in-hospital treatment, for a selected group of children, is not inferior to non-early discharge (five days or more, on average) in children with cancer and fever during neutropenia. Furthermore, we wanted to evaluate whether very early discharge (less than 24 hours, on average) is not inferior to early discharge, and whether very early discharge is not inferior to non-early discharge.

Background
Treatment with chemotherapy can cause a low white blood cell count (neutropenia) in children with cancer. Due to the high risk of bacterial infections and of a sudden and severe course of infections, standard care for children with cancer and fever during neutropenia consists of routine hospitalization and intravenous administration of broad-spectrum antibiotics (antibiotics that act against a wide range of disease-causing bacteria). However, causes of fever during neutropenia can be less serious; in a subgroup of these children lengthy in-hospital treatment might be unnecessary.

Study characteristics
The evidence is current to December 2015. The current review identified one study, Santolaya 2004, in which early discharge was compared to non-early discharge in this group of children, and one study, Brack 2012, in which very early discharge was compared to early discharge.

Key results
Early discharge did not appear to be less safe than non-early discharge in children with cancer and fever during neutropenia with a low risk for bacterial infections; there was no clear evidence of difference in treatment failure between the two groups. Moreover, the treatment costs in the early discharge group were lower than in the non-early discharge group. Regarding very early discharge, this did not appear to be less safe than early discharge; there was no clear evidence of difference in treatment failure between the two groups. Duration of treatment differed between very early discharge and early discharge; duration of intravenous antibiotic treatment was shorter in the very early discharge group, and duration of oral antibiotic treatment was shorter in the early discharge group, as compared to one another. However, there was no clear evidence of difference in total treatment duration of any antibiotic treatment between these groups.

Quality of the evidence
For both reported comparisons, the quality of the evidence was low. The included studies were relatively small with a low number of participants, thus it was possible that the absence of clear evidence of differences in the included studies could be due to, for example, the lack of power. Unfortunately, it was not possible to pool data in the two studies.

Conclusion
In conclusion, regarding both rehospitalization or adjustment of antibiotics (or both) and death, evidence was fairly limited; however, there was no evidence that early discharge was less safe than non-early discharge or very early discharge was less safe than early discharge of children with cancer and fever during neutropenia and a low risk for invasive bacterial infection. Future larger trials are needed to confirm or contradict these results.

Authors' conclusions: 

Very limited data were available regarding the safety of early discharge compared to non-early discharge from in-hospital treatment in children with cancer and febrile neutropenia and a low risk for invasive infection. The absence of clear evidence of differences in both studies could be due to lack of power.

Evidently, there are still profound gaps regarding very early and early discharge in children with cancer and febrile neutropenia. Future studies that assess this subject should have a large sample size and aim to establish uniform and objective criteria regarding the identification of a low-risk febrile neutropenic episode.

Read the full abstract...
Background: 

Chemotherapy-induced neutropenia is a common adverse effect in children with cancer. Due to the high relative risk of infections and infectious complications, standard care for children with cancer and febrile neutropenia consists of routine hospitalization and parenteral administration of broad-spectrum antibiotics. However, there are less serious causes of febrile neutropenia; in a subgroup of these children, lengthy in-hospital treatment might be unnecessary. Various research groups have studied the adjustment of standard care to shorten in-hospital treatment for children with cancer and febrile neutropenia at low risk for bacterial infections. However, most of these studies were not done in a randomized matter.

Objectives: 

To evaluate whether early discharge (mean/median of less than five days) from in-hospital treatment was not inferior to non-early discharge (mean/median of five days or more) and whether very early discharge (mean/median of less than 24 hours) was not inferior to early discharge, non-early discharge, or a combination of these, in children with cancer and febrile neutropenia.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (2015, issue 11), MEDLINE/PubMed (from 1945 to December 2015), EMBASE/Ovid (from 1980 to December 2015), the reference lists of relevant articles and review articles, and various conference proceedings (dependent on availability from 2005 to 2010 to 2013 to 2015). We scanned the International Standard Randomised Controlled Trials Number (ISRCTN) Register, the National Institute of Health Register for ongoing trials, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 9 January 2016.

Selection criteria: 

We included all randomized controlled trials and controlled clinical trials in which children with cancer and febrile neutropenia were divided in groups with different times of discharge.

Data collection and analysis: 

We used standard methods of Cochrane and its Childhood Cancer Group. Two independent review authors performed study selection, data extraction, and risk of bias assessment. We entered data extracted from the included studies into Review Manager 5 and undertook analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.

Main results: 

We included two randomized controlled trials assessing very early, early, non-early (or a combination of these) discharge in children with cancer and febrile neutropenia. We graded the evidence as low quality; we downgraded for risk of bias and imprecision. One study, Santolaya 2004, consisted of 149 randomized low-risk episodes and compared early discharge (mean/median of less than five days) to non-early discharge (mean/median of five days or more). This study found no clear evidence of difference in treatment failure (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.24 to 3.50, P value = 0.89 for rehospitalization or adjustment of antimicrobial treatment, or both; Fischer's exact P value = 0.477 for death) or duration of treatment (mean difference -0.3 days, 95% CI -1.22 to 0.62, P value = 0.52 for any antimicrobial treatment; mean difference -0.5 days, 95% CI -1.36 to 0.36, P value = 0.25 for intravenous antimicrobial treatment; mean difference 0.2 days, 95% CI -0.51 to 0.91, P value = 0.58 for oral antimicrobial treatment). Costs were lower in the early discharge group (mean difference USD -265, 95% CI USD -403.14 to USD -126.86, P value = 0.0002). The second included study, Brack 2012, consisted of 62 randomized low-risk episodes and compared very early discharge (mean/median of less than 24 hours) to early discharge (mean/median of less than five days). This study also found no clear evidence of difference in treatment failure (RR 0.54, 95% CI 0.15 to 1.89, P value = 0.34 for rehospitalization or adjustment of antimicrobial treatment (or both); Fischer's exact P value = 0.557 for death). Regarding duration of treatment, median duration of intravenous antimicrobial treatment was shorter in the very early discharge group (Wilcoxon's P value ≤ 0.001, stated in the study) and median duration of oral antimicrobial treatment was shorter in the early discharge group (Wilcoxon's P ≤ 0.001, stated in the study) as compared to one another. However, there was no clear evidence of difference in median duration of any antimicrobial treatment (Wilcoxon's P value = 0.34, stated in the study). Costs were not assessed in this study. Neither of the included studies assessed quality of life. Meta-analysis was not possible as the included studies assessed different discharge moments and used different risk stratification models.

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