Abstract

Background

Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment‐related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony‐stimulating factors (G(M)‐CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony‐stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken.

Objectives

To compare the efficacy and safety of G(M)‐CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy.

Search methods

We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full‐text and abstract publications. Two review authors independently screened search results.

Selection criteria

We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)‐CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full‐text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross‐over trials, quasi‐randomised trials and post‐hoc retrospective trials.

Data collection and analysis

Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician.

Main results

In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high‐dose chemotherapy and G‐CSF compared to antibiotics, a second one evaluating 155 patients with small‐cell lung cancer receiving GM‐CSF or antibiotics.

We judge the overall risk of bias as high in the G‐CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM‐CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.

For the trial comparing G‐CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection‐related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection‐related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.

There was no evidence of a difference in terms of median survival time in the trial comparing GM‐CSF and antibiotics. Two‐year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM‐CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM‐CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM‐CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non‐haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM‐CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection‐related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial.

Authors' conclusions

As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)‐CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Author(s)

Nicole Skoetz, Julia Bohlius, Andreas Engert, Ina Monsef, Oliver Blank, Jörg‐Janne Vehreschild

Abstract

Plain language summary

Prophylactic antibiotics or G(M)‐CSF for the prevention of infections in cancer patients undergoing chemotherapy

Review question

We reviewed the existing literature examining the efficacy and safety of granulocyte (macrophage) colony‐stimulating factors (G(M)‐CSF) compared to antibiotics to prevent infections for cancer patients receiving chemotherapy.

Background

Cancer treatment with chemotherapy (anti‐cancer drugs) disrupts the immune system and lowers white blood cell counts. This increases a person's risk of infection. Both G(M)‐CSF and antibiotics can reduce the risk of infection associated with cancer treatments. The review compared the efficacy of antibiotics to G(M)‐CSFs for the prevention of infection.

Study characteristics

We searched several medical databases and identified two randomised controlled trials (RCT) that met our inclusion criteria; no new trials were identified for this review update. One trial included 40 breast cancer patients receiving high‐dose chemotherapy. Eighteen patients received G‐CSF and 22 got antibiotics (ciprofloxacin and amphotericin) to prevent infection. Another trial evaluated GM‐CSF versus antibiotics in patients with small‐cell lung cancer, with 78 patients in the GM‐CSF arm and 77 patients in the antibiotics arm.

Key results

The study that analysed G‐CSF versus antibiotics did not report all cause mortality, microbiologically or clinically documented infections, severe infections, quality of life, or adverse events. We found no evidence of a difference between the two prophylactic options for the outcomes of infection‐related mortality (no patient died because of infection), or febrile neutropenia.

The trial that assessed GM‐CSF versus antibiotics did not found any evidence of a difference in all cause mortality, trial mortality, infections, or severe infections. The only difference between the two arms was found for the adverse event thrombocytopenia, favouring patients receiving antibiotics. Quality of life was not reported in this trial.

More research is needed to determine the best prevention against infection in cancer patients.

Quality of the evidence

The quality of the evidence for infection‐related mortality and frequency of febrile neutropenia in the G‐CSF trial was very low, because of the small number of patients that were evaluated, and the study design (high risk of bias). The trial that analysed GM‐CSF versus antibiotics reported overall survival, toxic deaths, infections, severe infections, and adverse events. Because of the very small number of patients included, we judged that the overall quality for all these outcomes was low.

The evidence is current to December 2015.

Author(s)

Nicole Skoetz, Julia Bohlius, Andreas Engert, Ina Monsef, Oliver Blank, Jörg‐Janne Vehreschild

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

There is insufficient direct evidence from randomised controlled trials to recommend one prophylaxis (G‐CSFs, GM‐CSFs, or antibiotics) over the other for cancer patients receiving myelotoxic chemotherapy.

Implications for research 

Large high quality trials comparing antibiotic prophylaxis to infection prophylaxis using G‐CSFs or GM‐CSFs are necessary in a wide range of cancer patients, to evaluate clinically important outcomes, like all cause and infection‐related mortality, incidence of febrile neutropenia, quality of life and adverse events.

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