Loeffen Erik A H, Te Poele Esther M, Tissing Wim J E, Boezen H Marike, de Bont Eveline S J M
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital / University Medical Center of Groningen, University of Groningen, PO Box 30.001, Groningen, Netherlands, 9700 RB.
Cochrane Database Syst Rev. 2016 Feb 22;2(2):CD008382. doi: 10.1002/14651858.CD008382.pub2.
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.
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.
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.
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.
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.
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.
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.
化疗引起的中性粒细胞减少是癌症患儿常见的不良反应。由于感染及感染性并发症的相对风险较高，对于患有癌症和发热性中性粒细胞减少症的患儿，标准治疗方案包括常规住院以及胃肠外给予广谱抗生素。然而，发热性中性粒细胞减少症还有一些不太严重的病因；在这些患儿的一个亚组中，可能无需进行长时间的住院治疗。多个研究团队已对标准治疗方案进行了研究，以缩短癌症和发热性中性粒细胞减少症且细菌感染低风险患儿的住院治疗时间。然而，这些研究大多并非采用随机方式进行。
评估癌症和发热性中性粒细胞减少症患儿早期出院（平均/中位数少于5天）是否不劣于非早期出院（平均/中位数为5天或更长时间），以及极早期出院（平均/中位数少于24小时）是否不劣于早期出院、非早期出院或这些方式的组合。
我们检索了Cochrane对照试验中心注册库（2015年第11期）、MEDLINE/PubMed（1945年至2015年12月）、EMBASE/Ovid（1980年至2015年12月）、相关文章和综述文章的参考文献列表以及各种会议论文集（取决于2005年至2010年、2013年至2015年是否可得）。我们于2016年1月9日检索了国际标准随机对照试验编号（ISRCTN）注册库、美国国立卫生研究院正在进行的试验注册库以及世界卫生组织（WHO）国际临床试验注册平台（ICTRP）。
我们纳入了所有将癌症和发热性中性粒细胞减少症患儿按不同出院时间分组的随机对照试验和对照临床试验。
我们采用了Cochrane及其儿童癌症小组的标准方法。两位独立的综述作者进行了研究选择、数据提取和偏倚风险评估。我们将从纳入研究中提取的数据录入Review Manager 5，并根据《Cochrane干预措施系统评价手册》的指南进行分析。
我们纳入了两项随机对照试验，评估癌症和发热性中性粒细胞减少症患儿的极早期、早期、非早期（或这些方式的组合）出院情况。我们将证据等级评定为低质量；我们因偏倚风险和不精确性而降低了等级。一项研究（Santolaya 2004）包含149个随机的低风险病例，比较了早期出院（平均/中位数少于5天）与非早期出院（平均/中位数为5天或更长时间）。该研究未发现治疗失败（再住院或调整抗菌治疗，或两者兼有；再住院或调整抗菌治疗的风险比（RR）为0.91，95%置信区间（CI）为0.24至3.50，P值 = 0.89；死亡的Fischer精确P值 = 0.477）或治疗持续时间（任何抗菌治疗的平均差值为 -0.3天，95% CI为 -1.22至0.62，P值 = 0.52；静脉抗菌治疗的平均差值为 -0.5天，95% CI为 -1.36至0.36，P值 = 0.25；口服抗菌治疗的平均差值为0.2天，95% CI为 -0.51至0.91，P值 = 0.58）存在明显差异的明确证据。早期出院组的费用较低（平均差值为 -265美元，95% CI为 -403.14美元至 -126.86美元，P值 = 0.0002）。第二项纳入研究（Brack 2012）包含62个随机的低风险病例，比较了极早期出院（平均/中位数少于24小时）与早期出院（平均/中位数少于5天）。该研究也未发现治疗失败（再住院或调整抗菌治疗（或两者兼有）的RR为0.54，95% CI为0.15至1.89，P值 = 0.34；死亡的Fischer精确P值 = 0.557）存在明显差异的明确证据。关于治疗持续时间，与早期出院组相比，极早期出院组静脉抗菌治疗的中位数持续时间较短（研究中指出Wilcoxon P值≤0.001），早期出院组口服抗菌治疗的中位数持续时间较短（研究中指出Wilcoxon P≤0.001）。然而，对于任何抗菌治疗的中位数持续时间，未发现明显差异的明确证据（研究中指出Wilcoxon P值 = 0.34）。该研究未评估费用。纳入的两项研究均未评估生活质量。由于纳入的研究评估的出院时间不同且使用的风险分层模型不同，因此无法进行Meta分析。
与癌症和发热性中性粒细胞减少症且侵袭性感染低风险患儿的非早期出院相比，关于早期出院安全性的可用数据非常有限。两项研究均未发现明显差异的明确证据可能是由于检验效能不足。显然，对于癌症和发热性中性粒细胞减少症患儿的极早期和早期出院，仍存在巨大差距。未来评估该主题的研究应具有大样本量，并旨在建立关于识别低风险发热性中性粒细胞减少症病例的统一且客观的标准。
