1 Department of Medicine E, Beilinson Campus, Rabin Medical Center, Petah Tiqva 49100; 2 Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, Israel
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Abstract |
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Objectives: To compare the efficacy of oral antibiotics versus iv antibiotic therapy in febrile neutropenic cancer patients.
Data sources: The Cochrane Library, the Cochrane Cancer Network Register of trials, EMBASE, LILACS and MEDLINE, databases for ongoing trials and the conference proceedings of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).
Study selection: Randomized controlled trials comparing oral antibiotic/s and iv antibiotic/s for the treatment of neutropenic cancer patients with fever.
Data collection: Two reviewers independently assessed trial eligibility, methodological quality and extracted all data. Data concerning mortality, treatment failures and adverse events were drawn from included studies assuming an intention-to-treat and per-protocol basis for the outcome measures whenever possible. Relative risks (RR) with their 95% confidence intervals (CI) for dichotomous data were estimated.
Main results: Fifteen trials (median mortality 0, range 0%8.8%) were included in the analyses. The mortality rate was similar comparing oral and iv antibiotic treatment (RR 0.83, 95% CI 0.491.41, 2224 patients). Treatment failure rates were also similar (RR 0.94, 95% CI 0.841.05, 15 trials). No significant heterogeneity was shown for the primary outcomes. This effect was stable in a wide range of patients. Quinolones alone or combined with other antibiotics were used with comparable results. Adverse reactions, mostly gastrointestinal, were more common with oral antibiotics.
Conclusions: Oral antibiotics may be safely offered to neutropenic patients with fever who are at low risk for mortality.
Keywords: neutropenic patients , antimicrobial drugs , fever
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Introduction |
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Clinical trials explored the feasibility of oral antibiotic treatment for low risk febrile neutropenia.10,11 Most of these trials were small and single centre. Thus, although reporting similar rates of success for oral and iv therapy, the superiority of an iv regimen could not be ruled out. We performed a systematic review and meta-analysis in an attempt to provide better evidence regarding the safety and efficacy of oral treatment as opposed to iv treatment.
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Methods |
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We have compared the efficacy of oral antibiotic/s versus iv antibiotic therapy in febrile neutropenic cancer patients. We also compared the efficacy of these treatment modalities in the following subgroups: patients with unexplained fever at presentation versus documented infection; absolute neutrophil count (ANC) of >0.1x109 cells/L versus below; solid tumour versus haematological malignancy and children versus adults.
Eligible studies were randomized trials, comparing any oral antibiotics with any iv antibiotics for the treatment of febrile neutropenia induced by chemotherapy in cancer patients, irrespective of language and publication status.
The primary outcomes were all-cause mortality at 30 days and treatment failure. Whenever all-cause mortality could not be obtained, infectious-related mortality was used. For the purpose of this review, treatment failure was defined as a composite end-point comprising one or more of the following: death; persistence, recurrence or worsening of clinical signs or symptoms of presenting infection; any addition to or modification of the assigned intervention.12,13 Secondary outcomes were: treatment failure other than modification of the primary intervention, lost to follow-up before end of study (dropouts). Adverse effects were defined as life-threatening or associated with permanent disability and those requiring discontinuation of therapy.
Search strategy
Relevant trials were identified by searching CENTRAL (Cochrane Library, issue 2, 2002), the Cochrane Cancer Network Register of trials (November 2002), EMBASE (January 19802002), LILACS (1982 to 2002) and MEDLINE (19662002) with the terms:
((fever*:ME OR febrile OR infection*:ME OR infect* OR sepsis*:ME) AND (neutropenia*:ME OR neutropen* OR neutropaen* OR granolucytopen* OR granolucytopaen* OR leukopen* OR leukopaen*) AND (oral OR per os) AND (intravenous OR parenteral) AND ((antibiotics*:ME OR antibiot* OR antimicrob* OR anti-microb* OR antibact* OR anti-infective agents*:ME) NOT decontamination*:ME))
References of all identified studies as well as major reviews were inspected to track down further studies. We searched conference proceedings and trial databases for ongoing and unpublished trials. Additionally, the first or corresponding author of each included study was contacted, as were pharmaceutical companies, for complementary information or information regarding unpublished trials.
Retrieval of studies and data
One reviewer inspected the abstract of each reference identified by the search and applied the inclusion criteria. For possibly relevant articles, the full article was obtained and inspected by two reviewers independently. They assessed the relevant articles for methodological quality and extracted data from included trials. This was conducted using the criteria described in the Cochrane handbook, which are based on the evidence of a strong association between poor allocation concealment and overestimation of effect.14,15 Data extractions were discussed, decisions documented and all authors of included studies were contacted for clarification. In case of disagreement between the two reviewers, a third reviewer extracted the data. All data were collected on an intention-to-treat basis whenever possible.
Statistical analysis
Relative risks with 95% confidence intervals for dichotomous data were calculated. Exclusions after randomization were reported.
Heterogeneity in the results of the trials was initially graphically inspected and assessed by calculating tests of heterogeneity (2 and I2). Heterogeneity was explored through stratifying by the above-defined patient subgroups (objectives), separating patients by different low risk criteria.
A fixed effect model was used unless significant heterogeneity (P<0.10) was detected, in which case the random effect model was used.
A funnel plot, estimating the precision of trials, was examined in order to estimate potential asymmetry that may indicate selection bias or methodological flaw in small studies. Publication bias was estimated also by the formal BeggMazumdar rank correlation test.16
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Results |
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The process used to identify eligible trials is described in Figure 1.
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The studies were performed during the years 19891999, and included 2511 randomized patients or episodes. Oral antibiotics were compared with intravenous, both given empirically and as the initial treatment (initial oral) in 10 trials. In the other five trials, all patients received iv antibiotics prior to oral therapy (sequential).47,49,52,53,55 In two sequential trials, patients were randomized at presentation, but switched to oral therapy if clinically stable 72 h later.47,49 The setting of therapy also varied. All patients were treated as outpatients in four trials.11,52,54,58 In three trials, patients randomized to oral therapy were treated as outpatients, whereas the control group was treated in hospital (Table 1).50,57,59
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Methodological quality of included studies
Adequate allocation concealment was employed in six trials. One trial was double-blinded48 and in another the outcomes assessors were blinded to the treatment arm.51 Duration of follow-up was pre-defined only in two trials.51,53 In the other trials, it had varied according to the length of neutropenic febrile episode. In two trials, the patients were followed for a pre-defined time after resolution fever. In the other trials, patients were followed until the end of the febrile neutropenic episode or the end of antibiotic treatment.
The unit of randomization was the patient in four trials10,49,51,59 and the episode of febrile neutropenia in the other trials. The later trials included 1430 episodes in 1017 patients.
Efficacy of oral antibiotics
Mortality (15 trials, 2224 patients). No difference in mortality between oral and iv treatment was demonstrated (all-cause mortality: RR 0.83, 95% CI 0.49 to 1.40; Figure 2).
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Adverse events. No trial reported death or permanent damage due to the study drug. Adverse effects that required discontinuation of the assigned antibiotic therapy were reported in 1110,11,4750,52,55,57 trials (RR 1.79, 95% CI 0.516.29; n=1536). Separate analysis of the initial oral studies revealed significantly more adverse events requiring discontinuation among orally treated patients (RR 6.65, 1.7525.33). This finding is explained by the high rates of gastrointestinal adverse events with oral antibiotics and with the fact that these events hamper oral but not iv treatment (post-protocol analysis: RR 3.01, 95% CI 0.999.12; n=607).
Resistance. Only three trials reported resistance by the microbial isolates to both antibiotic regimens. Four trials reported failure due to resistance;4951,57 there was no difference between oral and iv treatment.
Sensitivity analyses. Sensitivity analyses of studies with adequate and inadequate quality showed no significant impact on mortality or treatment failure. Sensitivity analyses on different case definitions showed similar relative risks: in the six trials that included patients with any source of infection, patients who were treated orally had RR 0.96, 95% CI 0.721.29 for treatment failure.10,11,47,49,54,56 Most of the trials included patients with haematological malignancy (but not acute leukaemia). The RR for treatment failure with oral therapy in those trials was 0.9, 95% CI 0.741.09. Treatment setting had no significant effect on failure. When analyses were performed according to oral antibiotic regimen, we observed no significant impact of quinolone treatment alone versus quinolones in combination with other antibiotics (Figure 4).
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Discussion |
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One limitation of the analysis is its inability to define the patients who may have been offered oral antibiotics. This is due to the variations in the inclusion and exclusion criteria. The difference in low risk criteria is not surprising: the concept of low risk neutropenic fever and its definition developed during the years in which the studies were performed. Different prognostic criteria evolved based on observational studies.6,7,9,6062 International collaboration had led to the development of a weighted scoring system identifying low risk patients,8 adopted by IDSA.5 Favourable factors are: the development of fever out of hospital, age below 60 years, no to moderate symptoms, no hypotension, no chronic bronchitis, no dehydration and either solid tumour or no history of fungal infection. While receiving conventional therapy this group had 1% mortality.
Low mortality rate led to wide confidence intervals in the absolute risk reduction. To confirm equivalence of two treatments, we should ideally be able to show that any estimate of risk included within the confidence interval lay within a pre-defined range of equivalence and had no clinical significance.63 In a population with an expected mortality of <1%, this uncertainty may have no real consequences.
For treatment failure, the confidence interval is narrower and probably has no clinical importance since failure means mainly a change in the antibiotic regimen.
According to the available data, oral antibiotic therapy can be safely offered to febrile children and adults with neutropenia who are haemodynamically stable, have no organ failure, can take oral medications, and do not have pneumonia, infection of a central line or a severe soft-tissue infection. These criteria stand in close relationship to those used in the guidelines of IDSA for the treatment of neutropenic patients. Oral treatment may improve the quality of life of cancer patients, reduce the complication associated with iv therapy and lower the costs of the treatment.
The analysis offered no data in support of a specific oral regimen, but in light of the preponderance of Gram-positive infections,5,62 the combination of a quinolone and a second drug active against Gram-positive bacteria (e.g., ampicillin/clavulanate) seems prudent.
A future trial of oral versus iv antibiotic treatment should include febrile neutropenic patients with mild and stable sepsis, regardless of their underlying disorder, source of infection or neutrophil count. Its sample size should be based on considerations of equivalence.63 The definitions of response and failure and the reported outcomes should be based on guidelines on methodology for clinical trials involving patients with fever and neutropenia.13,64,65
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Acknowledgements |
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We thank Mrs Mandy Collingwood and Mrs Vivien Garner of the Cochrane Gynaecological Cancer Review Group, for their helpful advice and assistance in obtaining articles.
Supported in part by an EU 5th Framework Grant (TREAT, IST 199911459) and by a grant from the Steering Committee for Research Promotion at Rabin Medical Center, Israel.
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Footnotes |
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References |
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