Summary of findings 1. Benefits and harms of CSF plus antibiotics versus antibiotics alone.
| CSF plus ATB compared to ATB alone for chemotherapy induced febrile neutropenia | |||||
| Population: people with chemotherapy‐induced febrile neutropenia Settings: in‐patient/hospital Intervention: CSF plus ATB Comparison: ATB alone | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | |
| Assumed risk | Corresponding risk | ||||
| ATB alone | CSF + ATB | ||||
| Overall mortality | Study population | HR 0.74 (0.47 to 1.16) | 1335 (13) | ⊕⊕⊝⊝ low1,2,3 | |
| 70 per 1000 | 52 per 1000 (33 to 80) | ||||
| Moderate | |||||
| 29 per 1000 | 22 per 1000 (14 to 34) | ||||
| Infection‐related mortality | Study population | RR 0.75 (0.47 to 1.20) | 897 (10) | ⊕⊕⊝⊝ low1,2,3 | |
| 56 per 1000 | 43 per 1000 (27 to 67) | ||||
| Moderate | |||||
| 22 per 1000 | 17 per 1000 (10 to 26) | ||||
| People hospitalized for > 10 days | Study population | RR 0.65 (0.44 to 0.95) | 1087 (7) | ⊕⊕⊝⊝ low3,4 | |
| 349 per 1000 | 227 per 1000 (153 to 331) | ||||
| Moderate | |||||
| 338 per 1000 | 220 per 1000 (149 to 321) | ||||
| Duration of grade IV neutropenia (lower values signify better outcomes) | The mean duration of grade IV neutropenia in the intervention groups was 1.70 standard deviations lower (2.65 to 0.76 lower) |
SMD ‐1.70 (‐2.65 to ‐0.76) |
1135 (9) | ⊕⊕⊝⊝ low3,5 | |
|
Time to recovery from fever (lower values signify better outcomes) |
The mean time to recovery from fever in the intervention groups was 0.49 standard deviations lower (0.9 to 0.09 lower) |
SMD ‐0.49 (‐0.9 to ‐0.09) |
966 (9) | ⊕⊕⊝⊝ low3,6 | |
|
Time to withdrawal from ATB (lower values signify better outcomes) |
The mean time to withdrawal from ATB in the intervention groups was 1.5 standard deviations lower (2.83 to 0.18 lower) |
SMD ‐1.5 (‐2.83 to ‐0.18) |
457 (3) | ⊕⊕⊝⊝ low3,7 | |
| Deep vein thrombosis | Study population | RR 1.68 (0.72 to 3.93) | 389 (4) | ⊕⊕⊝⊝ low1,3 | |
| 26 per 1000 | 43 per 1000 (18 to 101) | ||||
| Moderate | |||||
| 5 per 1000 | 8 per 1000 (4 to 20) | ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ATB: antibiotics; CI: confidence interval; HR: hazard ratio; RR: risk ratio; SMD: standardized mean difference | |||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | |||||
1 Seven of the included articles described an adequate method of randomization (Anaissie 1996; Aviles 1996; Garcia‐Carbonero 2001; Lopez‐Hernandez 2000; Riikonen 1994; Vellenga 1996; Yoshida 1999) and five reported adequate concealment of the sequence of allocation (Aviles 1996; Garcia‐Carbonero 2001; Maher 1994; Mayordomo 1995; Mitchell 1997). Seven trials were placebo controlled (Arnberg 1998; Biesma 1990; Maher 1994; Mayordomo 1995; Mitchell 1997; Riikonen 1994; Vellenga 1996). A sample size was preplanned in seven (Garcia‐Carbonero 2001; Maher 1994; Mayordomo 1995; Mitchell 1997; Ravaud 1998; Vellenga 1996; Rodriguez 2005), but the planned number was not reached in one trial (Ravaud 1998). Hence we downgraded the quality of evidence by 1 for the risk of bias (also see footnote # 2 below). 2 Of all the included trials only that by Aviles et al (Aviles 1996) appeared to show a benefit of CSF plus antibiotics compared with antibiotics alone for the outcome of overall mortality. It is important to note that 33% (15 of 45) of the events for this outcome in the control group were reported in this trial. These 15 deaths represent 33% (15 of 45) of the total of deaths in the control group among all trials. Similarly, there were 15 infection‐related deaths among the 471 participants randomized to the intervention group and 25 among 426 randomized to the control group. However, it is important to note that 60% (15 of 25) of the events in the control group were reported in one study (Aviles 1996). 3 A majority of the individual randomized controlled trials and the pooled estimates have wide CIs. We downgraded the quality of evidence by 1 for the observed imprecision.
4 Substantial heterogeneity was detected (P = 0.0009, I2 = 70%). As planned, we explored the possible causes of heterogeneity to determine if it was appropriate to pool the trials. All trials but one trial (Yoshida 1999) had a point estimate that favored the intervention group. This trial enrolled only people with hematological malignancies. We explored the impact of type of malignancy on number of participants hospitalized for more than 10 days (Subgroup analysis and investigation of heterogeneity: type of malignancy). The trials enrolling people with mixed cancers favored the use of CSF plus antibiotics (RR 0.64, 95% CI 0.45 to 0.89) compared with trial enrolling people with only hematological malignancies (RR 1.17, 95% CI 0.81 to 1.70) (test of interaction P = 0.02) for the outcome of number of participants hospitalized for more than 10 days (Analysis 5.1). We also noticed that only two trials reached statistical significance (Maher 1994; Mayordomo 1995). By inspecting the forest plot, we could detect that trial by Mayordomo et al (Mayordomo 1995) and Maher et al (Maher 1994) indicated a much stronger effect than that detected in all other trials. We therefore repeated our analysis, excluding these trials (Maher 1994; Mayordomo 1995). The exclusion resulted in a substantial reduction in the statistical heterogeneity (I2 = 48%; P = 0.10) and the significance of the effect of CSF plus antibiotics on this outcome disappeared (RR 0.85, 95% CI = 0.61 to 1.17; P = 0.32). Hence we downgraded the quality of evidence by 1 for the observed inconsistency.
5 Considerable heterogeneity was detected (P value < 0.00001, I2 = 98%). In a subgroup analysis according to CSF type, G‐CSF showed a statistically significantly stronger beneficial effect than GM‐CSF for the outcome of duration of grade IV neutropenia (Analysis 3.3). Nonetheless, we downgraded the quality of evidence by 1 for the observed inconsistency.
6 Considerable heterogeneity was detected (P value < 0.00001, I2 = 89%). We downgraded the quality of evidence by 1 for the observed inconsistency.
7 Considerable heterogeneity was detected (P value < 0.00001, I2 = 97%). We downgraded the quality of evidence by 1 for the observed inconsistency. We noted that in all of these trials the mean/median duration of ATB use was similar (mean of 5 days) among patients receiving CSF. However, the high precision observed around the effect size in the trial by Garcio‐Carbonero et al (Garcia‐Carbonero 2001) compared with other two trial estimates was potentially leading to the substantial heterogeneity. The heterogeneity disappeared completely once we removed this trial from the analysis (P value = 0.72, I2 = 0%) and the overall effect still showed benefit with the use of CSF plus ATB compared with ATB alone.