Reducing the risk of septic complications of anticancer treatment

National Collaborating Centre for Cancer (UK)

5Reducing the risk of septic complications of anticancer treatment

Increasing depth and duration of neutropenia increases the risk of infection. One approach to reducing the risk of life-threatening neutropenic sepsis is to prevent or reduce the likelihood of infection, another is to prevent or moderate the degree of neutropenia.

The objective of this chapter is to evaluate the role of growth factors and/or antibiotics to prevent neutropenic sepsis.

5.1. Preventing the septic complications of anticancer treatment

The likelihood of infection may be reduced by the prophylactic use of antibiotics, chosen to cover the most likely pathogens, and the time period of greatest risk for infection. The most serious bacterial infections are likely to arise from gram-negative organisms, but as the duration and degree of immunocompromise increases, significant infections can arise from other organisms too. Typical antibiotics used for prophylaxis include the quinolones, and historically cotrimoxazole. These are given orally, but may cause diarrhoea, vomiting or allergic reaction. There are concerns that the use of prophylactic antibiotics may lead to antibiotic resistance in the local community.

Granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) raise neutrophil counts, and shorten the duration of neutropenia, by stimulating the bone marrow to produce neutrophils. However, side effects include bone pain, headache and nausea. G-CSF and GM-CSF must be given daily by injection, and this may lead to uncomfortable local reactions. Long acting formulations which are given infrequently are available but are more expensive.

Either of these strategies may be used in patients regardless of whether they have experienced neutropenic sepsis or not. This is described as primary prophylaxis. An alternative approach is to use either of these strategies only in patients who have experienced neutropenic sepsis. This is described as secondary prophylaxis.

Clinical question: Does prophylactic treatment with growth factors, granulocyte infusion and/or antibiotics improve outcomes in patients at risk of neutropenic sepsis?

Clinical evidence (see also full evidence review)

Evidence statements for primary prophylaxis with G(M)-CSF versus no primary prophylaxis with G(M)-CSF

The evidence for primary prophylaxis with colony stimulating factors comes from systematic reviews of randomised trials by Sung, et al., (2007), Bohlius, et al., (2008) and Cooper, et al., (2011). This evidence is summarised in Table 5.1.

Table 5.1

GRADE profile: Is primary prophylaxis with G(M)-CSF (with or without antibiotics) more effective than no primary prophylaxis with G(M)-CSF (with or without antibiotics) at improving outcomes in patients at risk of neutropenic sepsis.

Mortality

There was high quality evidence that primary prophylaxis using G(M)-CSF did not reduce short-term all cause mortality when compared to no primary prophylaxis. No reduction in short-term mortality with G(M)-CSF was seen in subgroup analyses according to age group (paediatric, adult or elderly), type of cancer treatment (leukaemia, lymphoma/solid tumour or stem cell transplant) use of prophylactic antibiotics, colony stimulating factor type (G-CSF or GM-CSF).,

Febrile neutropenia

There was moderate quality evidence that prophylaxis using G(M)-CSF reduced the rate of febrile neutropenia when compared to no prophylaxis. The pooled estimate suggested an episode of febrile neutropenia would be prevented for every nine chemotherapy cycles that used G(M)-CSF prophylaxis.

Moderate quality evidence from subgroup analyses suggested that the effectiveness of prophylaxis with colony stimulating factors may vary according to the type of cancer treatment. In the subgroup of leukaemia studies, G(M)-CSF would need to be used for 13 cycles to prevent an additional episode of febrile neutropenia. In solid tumour/lymphoma studies the corresponding number of cycles was nine. In stem cell transplant studies there was serious uncertainty about whether G(M)-CSF helps prevent febrile neutropenia.

Antibiotic resistance

Antibiotic resistance was not reported in the included systematic reviews (Sung, et al., 2007; Bohlius, et al., 2008 and Cooper, et al., 2011).

Length of hospital stay

There was moderate quality evidence that the use of prophylactic G(M)-CSF was associated with a shorter hospital stay: the mean hospital stay was 2.41 days shorter with G(M)-CSF prophylaxis than without.

Quality of life

Quality of life was not reported in the included systematic reviews (Sung, et al., 2007; Bohlius, et al., 2008 and Cooper, et al., 2011).

Evidence statements for primary prophylaxis with G(M)-CSF plus antibiotic (quinolone or cotrimoxazole) versus primary prophylaxis with antibiotic

The trials were identified from the systematic review by Sung, et al., (2007) and from the list of excluded studies in a Cochrane review of prophylactic antibiotics versus G-CSF for the prevention of infections and improvement of survival in cancer patients undergoing chemotherapy (Herbst, et al., 2009 ). Most (18/27) of the trials used cotrimoxazole only (specifically for Pneumocystis pneumonia prophylaxis) – these were analysed separately from the nine trials that used quinolones. Three trials that used both quinolones and cotrimoxazole were included in the quinolone group for analysis. The trials were not designed to test the interaction of G(M)-CSF with antibiotics – rather prophylactic antibiotics were part of standard care (many of the these trials also used antiviral and antifungal prophylaxis). This evidence is summarised in Table 5.2.

Table 5.2

GRADE profile: Is primary prophylaxis with G(M)-CSF plus antibiotics more effective than primary prophylaxis with antibiotics at improving outcomes for patients at risk of neutropenic sepsis.

Mortality and febrile neutropenia

The evidence was of low quality for febrile neutropenia and moderate quality for short term mortality from any cause. There was uncertainty as to whether primary prophylaxis with G(M)-CSF plus quinolone or quinolone alone was better in terms of these outcomes due to the wide confidence intervals of the pooled estimates.

Infectious mortality

Moderate quality evidence suggested that infectious mortality was lower when G(M)-CSF plus quinolone was used for prophylaxis than with quinolone.

Antibiotic resistance, length of hospital stay, quality of life

These outcomes were not reported for this subgroup of studies in Sung, et al., (2007).

Evidence statements for primary prophylaxis with antibiotic (ciprofloxacin, levofloxacin, ofloxacin or cotrimoxazole) versus no primary prophylaxis

The evidence came from a Cochrane review of antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following anticancer treatment by Gafter-Gvili, et al., (2005). Data from trials of ciprofloxacin, levofloxacin, ofloxacin or cotrimoxazole were extracted from this review and analysed. Evidence about colonisation with resistant bacteria came from a second systematic review by the same authors (Gafter-Gvili, et al., 2007). An additional trial (Rahman and Khan, 2009) of levofloxacin prophylaxis was identified in our literature search. The evidence is summarised in Table 5.3.

Table 5.3

GRADE profile: Is primary prophylaxis with antibiotics more effective than no primary prophylaxis at improving outcomes in patients at risk of neutropenic sepsis.

Mortality

There was moderate quality evidence that prophylactic quinolones (ciprofloxacin or levofloxacin) reduced short-term all cause mortality when compared with no prophylaxis. From the pooled estimate, 59 patients would need prophylactic quinolones to prevent one additional death.

No ofloxacin studies reported the rates of all cause mortality.

Febrile neutropenia

The review analysed the rates of febrile neutropenia by patient (rather than by cycle). When patient rates were not reported, febrile episodes were used for the numerator. There was moderate quality evidence that antibiotic prophylaxis reduced the rate of febrile neutropenia, however there was inconsistency between individual study's estimates of effectiveness.

Subgroup analysis according to antibiotic suggested that levofloxacin, ofloxacin and cotrimoxazole might be more effective than ciprofloxacin in preventing febrile neutropenia.

However, even after grouping studies according to antibiotic used, there was still heterogeneity within the ofloxacin and cotrimoxazole groups.

The highest quality evidence came from the three levofloxacin trials. The pooled estimate from these trials suggested that 11 patients would need antibiotic prophylaxis to prevent one additional episode of febrile neutropenia.

Antibiotic resistance

There was moderate quality evidence that infection with bacteria resistant to the antibiotic used for prophylaxis was more likely in patients receiving antibiotic prophylaxis. The pooled estimate suggested an additional resistant infection for every 77 patients who received antibiotic prophylaxis.

Low quality evidence from four quinolone studies suggests uncertainty about the effect of quinolone prophylaxis on the rate of infection with bacteria resistant to quinolones.

Two quinolone trials reported only 8 cases of colonisation with resistant bacteria, in 93 patients. Low quality evidence suggests that colonisation with bacteria resistant to quinolones is more likely in patients who had received quinolone prophylaxis. It is impossible to get an accurate estimate of the impact of antibiotic prophylaxis on resistant colonisation with such a low number of events.

None of the trials reported the rates of colonisation with resistant bacteria before antibiotic prophylaxis or how these related to rates following prophylaxis.

Length of hospital stay

Although the Gafter-Gvili, et al., (2005) review considered this outcome, data on the length of hospital stay were too sparse to allow analysis

Quality of life

Quality of life was not considered as an outcome in the systematic review.

Evidence statements for primary prophylaxis with quinolone (ciprofloxacin, levofloxacin or ofloxacin) versus primary prophylaxis with cotrimoxazole

Evidence came from a Cochrane review of antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following anticancer treatment by Gafter-Gvili, et al., (2005). Evidence about colonisation with resistant bacteria came from a second systematic review by the same authors (Gafter-Gvili, et al., 2007). Data from trials comparing ciprofloxacin, Levofloxacin and ofloxacin to cotrimoxazole was extracted and analysed. The evidence is summarised in Table 5.4.

Table 5.4

GRADE profile: Is primary prophylaxis with quinolone more effective than primary prophylaxis with cotrimoxazole at improving outcomes in patients at risk of neutropenic sepsis.

Mortality

There was uncertainty as to whether prophylaxis with quinolones or cotrimoxazole was better in terms of short-term mortality. The 95% confidence intervals of the pooled estimate was wide enough to include the possibility that either antibiotic was significantly better than the other.

Febrile neutropenia

There was low quality evidence to suggest that prophylaxis of febrile neutropenia was more effective with ofloxacin than with cotrimoxazole. There was uncertainty about whether ciprofloxacin was more effective than cotrimoxazole, and there were no studies comparing levofloxacin with cotrimoxazole.

Antibiotic resistance

Low quality evidence suggested both infection and colonisation with bacteria resistant to the antibiotic used for prophylaxis was more likely with cotrimoxazole than with a quinolone.

Length of hospital stay and quality of life

Data on length of stay were sparse and not analysed. Quality of life was not reported

Evidence statements for primary prophylaxis with G(M)-CSF versus antibiotics

Evidence came from a Cochrane review of prophylactic antibiotics or G-CSF for the prevention of infections and improvement of survival in cancer patients undergoing chemotherapy (Herbst, et al., 2009). This review included two randomised trials directly comparing G(M)-CSF with antibiotics, remarkably few given the large number of trials comparing primary prophylaxis with G(M)-CSF or antibiotics to no primary prophylaxis. Schroeder. et al., (1999) compared G-CSF to ciprofloxacin plus amphotericin-B, Sculier, et al., (2001) compared GM-CSF to cotrimoxazole. The evidence is summarised in Table 5.5.

Table 5.5

GRADE profile: Is primary prophylaxis with G(M)-CSF more effective than primary prophylaxis with antibiotics at improving outcomes for patients at risk of neutropenic sepsis.

Mortality

One trial reported short term mortality. Due to the very low number of events there was serious uncertainty and it is not possible to conclude that the treatments are equivalent or that one is superior to the other.

Febrile neutropenia

One trial reported febrile neutropenia. Due to the very low number of events there was serious uncertainty and it is not possible to conclude that the treatments are equivalent or that one is superior to the other.

Antibiotic resistance

This outcome was not considered in the systematic review.

Length of hospital stay

One trial reported the median length of hospital stay was 6 days with G-CSF compared with 7 days with antibiotic prophylaxis. This difference was not statistically significant.

Quality of life

Neither of the trials reported this outcome.

Evidence statements for primary prophylaxis with pegfilgrastim versus filgrastim

Evidence came from a systematic review and meta-analysis of prophylactic G-CSFs which included a comparison of pegfilgrastim versus filgrastim for the prevention of neutropenia in adult cancer patients with solid tumours or lymphoma undergoing chemotherapy (Cooper, et al., 2011). This review included five randomised trials. The literature search identified an additional phase II randomised trial comparing pegfilgrastim to filgrastim for prophylaxis in children with sarcoma receiving chemotherapy (Spunt, et al., 2010). The evidence is summarised in Table 5.6.

Table 5.6

GRADE profile: Is primary prophylaxis with pegfilgrastim more effective than primary prophylaxis with filgrastim at improving outcomes for patients at risk of neutropenic sepsis.

Short term mortality

Short term mortality was not considered in Cooper, et al., (2011). One trial included in the systematic review reported mortality, but there was only one death (in the filgrastim group). Spunt, et al., (2010) did not report mortality.

Febrile neutropenia

Low quality evidence from five randomised trials (Cooper, et al., 2011) suggested pegfilgrastim was more effective than filgrastim in the prevention of febrile neutropenia, RR = 0.66 (95% C.I. 0.44 to 0.98).

Antibiotic resistance, length of hospital stay and quality of life

These outcomes were not considered in the systematic review.

Evidence statements for primary prophylaxis with granulocyte infusion versus no prophylaxis with granulocyte infusion

Evidence came from a Cochrane review of granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction (Massey, et al., 2009). This review included ten trials, all but one of which were carried out before 1988. The evidence is summarised in Table 5.7.

Table 5.7

GRADE profile: Is primary prophylaxis with granulocyte infusion more effective than no such prophylaxis at improving outcomes in patients at risk of neutropenic sepsis.

Mortality

Due to the relatively low number of events, there was uncertainty as to whether prophylactic granulocyte infusions reduce short-term all cause mortality in this population.

Febrile neutropenia

Due to the relatively low number of events, there was uncertainty as to whether prophylactic granulocyte infusions reduce the rate of febrile neutropenia in this population.

Antibiotic resistance

This outcome was not considered in the systematic review.

Length of hospital stay

Massey, et al., (2009) found little consistency in the reporting of duration of treatment and length of hospital stay, and chose not analyse this outcome further.

Quality of life

No trials reported this outcome.

Evidence statements for secondary prophylaxis with G(M)-CSF versus placebo or nothing (with or without antibiotics)

The literature search identified one randomised trial (Leonard, et al., 2009) published in abstract form only. This trial compared secondary prophylaxis using G-CSF with standard management (dose delay or reduction) in patients with early stage breast cancer receiving anthracyline or anthracycline-taxane sequential regimes. The evidence is summarised in Table 5.8.

Table 5.8

GRADE profile: Is secondary prophylaxis with G(M)-CSF more effective than no secondary prophylaxis at improving outcomes in patients with a prior episode of neutropenic sepsis.

Incidence of neutropenic sepsis

The rate of neutropenic sepsis was not reported. The trial reported the rate of neutropenic events, indirectly related to neutropenic sepsis and for this reason the evidence was considered low quality. The evidence suggested approximately two patients would need secondary prophylaxis with G-CSF to prevent one additional neutropenic event.

Overtreatment, death, critical care, length of stay, duration of fever, quality of life

These outcomes were not reported.

Evidence statements for secondary prophylaxis with antibiotics versus no secondary prophylaxis (with or without G(M)-CSF)

No trials of antibiotics for secondary prophylaxis were identified. One low quality randomised trial compared G-CSF plus ciprofloxacin or ofloxacin to G-CSF alone for secondary prophylaxis (Maiche and Muhonen, 1993). The evidence is summarised in Table 5.9.

Table 5.9

GRADE profile: Is secondary prophylaxis with quinolone plus G-CSF more effective than secondary prophylaxis with G-CSF alone at improving outcomes in patients with a prior episode of neutropenic sepsis.

Incidence of neutropenic sepsis

The rate of neutropenic sepsis was not reported, but Maiche and Muhonen (1993) reported the rate of documented infections. There was uncertainty as to whether prophylaxis with antibiotics plus G-CSF was more effective than G-CSF alone in preventing documented infection, due to the low number of documented infections and small size of the study.

Overtreatment, death, critical care, length of stay, duration of fever, quality of life

These outcomes were not reported.

Evidence statements for secondary prophylaxis with G-CSF versus antibiotics for secondary prophylaxis

No trials were identified.

Cost-effectiveness evidence for primary and secondary prophylaxis (see also full evidence review)

Ten studies were included for this topic. The results of all included studies are summarised in Table 5.10.

Table 5.10

Modified GRADE profile: Cost effectivness of primary and secondary prophylaxis.

Study quality and results

All included papers were deemed partially applicable to this guideline. The most common reason for partial applicability was that the analyses did not include all options considered relevant for the topic. For example, most economic studies about G(M)-CSF omit quinolones. Other reasons for partial applicability included: analysis conducted in countries other than the UK, health effects not expressed in QALYs.

Seven papers were deemed to have very serious limitations. The most common reason for serious limitation was that the analyses considered the combined effectiveness of chemotherapy and G(M)-CSF, but did not count the cost of chemotherapy (Borget, et al., (2009); Danova, et al., (2008); Liu, et al., (2009); Lyman, (2009 a); Lyman, (2009 b); Ramsey, (2009). except Whyte, et al., (2011) is the only study that counted the cost of chemotherapy. However this study was also deemed to have very serious limitations as it did not use data from the best available source (ideally data should come from a recently conducted systematic review); and the estimates of clinical data used in Whyte, et al., (2011) differ substantively from the data reported by best available evidence (Note 28, Table 5.10)

The other three papers were deemed to have potentially serious limitations (Lathia, et al., 2009; Timmer-Bonte, et al., 2008; Timmer-Bonte, et al., 2006). The most common reason for potentially serious limitation was that the analyses did not use data from the best available source (ideally data should come from a recently conducted systematic review), but are similar in magnitude to the best available estimates.

Evidence statements

Eight studies were identified for patients with a solid tumour and two studies for patients with non-Hodgkin lymphoma. No economic evidence has been identified for patients with other types of cancer.

Solid tumour (adult)

Six out of the ten included studies looked at female patients with stage II breast cancer with at least 20% risk of febrile neutropenia. All six studies had conflicts of interest. Four of these papers (Borget, et al., 2009; Danova, et al., 2008; Liu, et al., 2009; Lyman, 2009 (b)) compared primary PEG-G-CSF G(M)-CSF with primary PEG-G-CSF; and all four papers reported PEG-G-CSF to be more cost-effective than G(M)-CSF. One paper (Ramsey, 2009) compared primary PEG-G-CSF with secondary PEG-G-CSF and reported that the latter strategy was more cost-effective. Only one study (Whyte, et al., 2011) compared different types of G(M)-CSF with nothing/placebo; this paper reported that at NICE willingness-to-pay threshold of £20,000 per QALY:

for patients with a febrile neutropenia risk level of 11% -37%, secondary PEG-G-CSF is the most cost-effective strategy.
for patients with a febrile neutropenia risk greater than 38%, primary PEG-G-CSF is the most cost-effective strategy.

Two of the ten papers identified looked at patients with small-cell lung cancer with at least 20% risk of febrile neutropenia. Both papers compared G(M)-CSF with quinolones against quinolones alone; one paper (Timmer-Bonte, et al., 2006) looked at primary prophylaxis while another (Timmer-Bonte, et al., 2008) looked at secondary prophylaxis. Both papers showed that G(M)-CSF with quinolones was more clinically effective than quinolones alone, but was associated with a very high ICER (£0.29¹⁰ million per febrile neutropenia free cycle (Timmer-Bonte, et al., 2008) and £329.28¹¹ per percent decrease of the probability of febrile neutropenia (Timmer-Bonte, et al., 2006). No conflicts of interest have been declared for these two papers.

Non-Hodgkin lymphoma (adult)

Two out of ten included studies looked at elderly patients with non-Hodgkin lymphoma with at least 20% risk of febrile neutropenia. The base-case analysis for both studies considered a cohort of 64-year-old men and women. Lyman, (2009)(a) compared primary G(M)-CSF with PEG-G-CSF, and reported that PEG-G-CSF was more cost-effective. Lathia, (2009) compared three prophylaxis strategies: primary (M)-CSF, primary PEG-G-CSF and nothing/placebo, and reported that the ICER associated with G(M)-CSF and PEG-G-CSF is £0.99¹² million/QALY and £2.52¹² million/QALY separately, compared to nothing/placebo.

Health economic evaluation (see also Appendix A)

Because of the large patient group covered by this topic and the potentially significant difference in cost of different treatment options this topic is identified as a high priority for economic analysis. A systematic review of the economic evidence was conducted, a summary of which is presented in the previous section. All included studies were deemed to be partially applicable to this topic, and deemed to have very serious or potentially serious limitations. No studies were found which directly addressed our question. As a result, de novo models have been built to inform recommendations.

Aim

The aim of this economic analysis was to examine which of the following prophylactic strategies is the most cost-effective for cancer patients who are receiving chemotherapy

Nothing/placebo
Primary prophylaxis with quinolones
Primary prophylaxis with G-CSF
Primary prophylaxis with G-CSF and quinolones
Primary prophylaxis with PEG-G-CSF
Secondary prophylaxis with quinolones
Secondary prophylaxis with G-CSF
Secondary prophylaxis with G-CSF and quinolones
Secondary prophylaxis with PEG-G-CSF

Evidence was reported for both quinolones and cotrimoxazole as antibiotic prophylaxis. However the GDG chose to focus on the evidence related to quinolones because of concerns that changing anti-microbial resistance patterns meant the cotrimoxazole trials may no longer be applicable (Gafter-Gvili, et al., 2005).

A subgroup analysis was conducted for the following three patient groups:

Patients with a Solid tumour (aged over 18 years)
Patients with Non-Hodgkin lymphoma (aged over 18 years)
Patients with Hodgkin lymphoma (aged over 18 years)

The economic analysis does not cover:

Cancer patients whose chemotherapy regimen includes G-CSF.
Cancer patients with planned inpatient treatment of greater than 10-days post-chemotherapy. It is acknowledged that the costs of prophylaxis and treatment of neutropenic sepsis for inpatient-only management are lower than outpatient management.
Paediatric cancer patients (aged less than 18 years). Due to considerable clinical heterogeneity in the treatment regimens for this patient group, and a paucity of direct evidence, a representative model for economic analysis could not be built
The impact of different prophylactic strategies on subsequent courses of chemotherapy. The consequence of this bias is discussed in detail in section A9.2.3.
Antibiotic resistance. The best available evidences identified to address the issue of antibiotic resistance caused by use of quinolones was derived from two systematic reviews: one was a review conducted for this guideline (see Page 79-83); and the other was a Cochrane review undertaken by Gafter-Gvili, et al., (2005). The conclusions of these two reviews were very similar. After use of quinolones, although there is an increase in colonisation with bacteria resistant to quinolones, there was no statistically significant increase in the number of infections caused by pathogens resistant to quinolones. The GDG were aware of the potential limitations of these two reviews but could not find any better evidence to answer the clinical question. Therefore the GDG decided to qualitatively consider the potential increase in antibiotic resistance and its impact on cancer patients when agreeing their recommendations, instead of quantitatively model it in the economic analysis.

Model structure

Decision trees are used to reflect key events in the clinical pathway in order to compare costs and health effects for the interventions of interest. In this economic analysis, two decision trees were constructed to cover two different populations:

model A for adult patients with Hodgkin lymphoma, and
model B for adult patients with a solid tumour or non-Hodgkin lymphoma.

The details of both models can be found below. A Markov process was embedded in both decision trees to model the recurrence of neutropenic sepsis within one course of chemotherapy.

Model A: ‘Continue to receive full dose chemotherapy’

This model assumes patients will continue to receive full-dose chemotherapy regardless of previous episodes of neutropenic sepsis.

Model B: ‘Dose-reduction chemotherapy’

This model assumes that if patients develop one episode of neutropenic sepsis, they will then receive dose-reduction chemotherapy. If they develop two episodes of neutropenic sepsis chemotherapy will be discontinued.

The time horizon of both models was one course of chemotherapy as the GDG were only interested in short-term outcomes.

The volume of clinical data to inform the relative risk of overall mortality (each prophylactic strategy versus nothing/placebo) was very sparse for the three patient subgroups included in the model. What's more, of the studies that report this outcome their quality was assessed by GRADE as low since none were designed to investigate the effect of GCSF on short-term mortality and the death rate between different arms was low. The GDG decided to assume that the overall mortality would be the same for each prophylactic strategy, and only looked at the efficacy of each strategy in terms of preventing neutropenic sepsis. Since the baseline short-term overall mortality rate for our target population group is normally very low; unless there were any prophylactic strategies that could significantly reduce short-term overall mortality, this bias is unlikely to change our conclusion.

Model inputs

Cost-effectiveness analysis requires clinical evidence, health-related preferences (utilities), healthcare resource use and costs. High quality evidence on all relevant parameters was essential; however these data were not always available. Where published evidence was sparse, the expert opinion of the GDG was used to estimate relevant parameters. To test the robustness of the results of the cost-effectiveness analysis, a series of sensitivity analysis were undertaken.

The effectiveness of each prophylactic strategy in terms of incidence of neutropenic sepsis, and short-term overall mortality, were obtained from the systematic reviews of the clinical evidence conducted for this topic (See Appendix 4 of the full evidence review).

Utility weights were required to estimate quality adjusted life years (QALYs). Estimates of health state utility for cancer patients with and without neutropenic sepsis were obtained from published studies (Brown, 2001).

The costs considered in this analysis were those relevant to the UK NHS, and included the cost of each prophylactic strategy, the costs of diagnostic investigation, and the costs of inpatient/outpatient treatment. Unit costs were based on British National Formulary (BNF 62), NHS reference cost (2009-10) and the Unit Costs of Health and Social Care (Curtis, 2010). The cost of chemotherapy was not included; as the economic model was only looking at the prevention and treatment of neutropenic sepsis.

Due to the short time horizon of the base-case model (less than 1 year), costs and health outcomes were not discounted.

Sensitivity Analysis

Three different kinds of sensitivity analysis were conducted to test the robustness of the results for each economic model. These were structural sensitivity analysis (for patients with a solid tumour and non-Hodgkin lymphoma only), probabilistic sensitivity analysis and one-way sensitivity analysis.

For each model, over sixteen scenarios were considered and are detailed below:

Number of cycles of chemotherapy (varies for each patient subgroup)
Baseline risk of neutropenic sepsis per chemotherapy cycle: Cycle 2 onwards¹³ (5 - 100%)
Relative risk of a neutropenic sepsis episode: Cycle 1 versus Cycle 2 onwards (1-10)
Relative risk of a neutropenic sepsis episode: previous neutropenic sepsis versus no previous neutropenic sepsis (1-10)
Relative risk of a neutropenic sepsis episode: each prophylactic strategy versus nothing/placebo (0.1 – 0.95)
Probability of self administrating PEG-G-CSF or G(M)-CSF (0-100%)
Probability of using an ambulance for patients with neutropenic sepsis (0-100%)
Probability of patients with neutropenic sepsis who are at high risk of serious adverse events (varies for each patient subgroup)
Days of using G(M)-CSF for each cycle of chemotherapy (5-11 days)
Days of inpatient treatment for neutropenic sepsis patients at low-risk of serious adverse events (1-6 days)
Days of inpatient treatment for neutropenic sepsis patients at high-risk of serious adverse events (6-14 days)
Cost per hospital bed day (£100 - £1000)
Daily cost of G(M)-CSF per person (£60.69¹⁴ – £98.57¹⁵)
Drug discounts of PEG-G-CSF and G(M)-CSF (0% - 90%)
Utility decrement due to inpatient treatment of neutropenic sepsis (0.14-0.38)
Utility decrement due to outpatient treatment of neutropenic sepsis (0-0.15).

Results

Adult/elderly patients with a solid tumour who can take fluoroquinolone

For adult patients with a solid tumour and who can take quinolone clinical evidence was available for all nine strategies of interest (Section A3.1.2). Compared to quinolone alone, G(M)-CSF and G(M)-CSF + quinolone are more expensive and less effective in terms of preventing neutropenic sepsis. Therefore all primary and secondary prophylactic strategies involving G(M)-CSF and G(M)-CSF + quinolone were excluded from the analysis. As a result cost-effectiveness was only formally examined for the following five strategies:

Nothing/placebo
Primary prophylaxis with quinolone
Secondary prophylaxis with quinolone
Primary prophylaxis with PEG-G-CSF
Secondary prophylaxis with PEG-G-CSF

The incremental costs and incremental QALYs in the base case analysis for each of the five strategies are summarised in Table 5.11. Taking primary prophylaxis with quinolone as the reference (least expensive) strategy, all other strategies were shown to be less effective and also more costly except primary prophylaxis with PEG-G-CSF. Compared to the reference strategy, use of primary PEG-G-CSF produces 3.3×10^–4 more QALYs and incurs £1,899.8 in additional costs. This yields an incremental cost-effectiveness ratio (ICER) of £5.7 million/QALY, which exceeds the NICE willingness to pay (WTP) threshold of £20,000/QALY. Therefore primary prophylaxis with PEG-G-CSF was considered not to be cost effective. At a willingness to pay (WTP) threshold of £20,000/QALY, primary prophylaxis with a quinolone is the most cost-effective strategy. This conclusion was robust to structural sensitivity analysis and all one-way sensitivity analysis tested (Section A4.2) except for relative risk of neutropenic sepsis (quinolones versus nothing/placebo).

Table 5.11

Incremental costs and effectiveness by treatment strategy for solid tumour patients who can take quinolone (baseline risk of neutropenic sepsis of one course of chemotherapy: 34.41%).

When the relative risk of neutropenic sepsis (quinolones versus nothing/placebo) was above 0.787, nothing/placebo became the most cost-effective strategy, at a WTP threshold of £20,000/QALY. Primary or secondary prophylaxis with PEG-G-CSF is never the most cost-effective strategy, even when extreme scenarios were considered, for example: 100% risk of neutropenic sepsis per cycle of chemotherapy, 90% drug discount of PEG-G-CSF, extended length of hospital stay for neutropenic sepsis patients (6-day for low-risk patients and 14-day for high-risk patients) etc.

The result of the probabilistic sensitivity analysis shows that the probability of primary prophylaxis with quinolone becoming cost-effective is always 100%, at a willingness to pay between £10,000 to £40,000 per QALY.

Adult/elderly patients with a solid tumour who cannot take fluoroquinolone

For adult patients with a solid tumour who cannot take quinolone, cost-effectiveness was only formally examined for the following strategies (all strategies containing quinolone were excluded):

Nothing/placebo
Primary prophylaxis with G(M)-CSF
Secondary prophylaxis with G(M)-CSF
Primary prophylaxis with PEG-G-CSF
Secondary prophylaxis with PEG-G-CSF.

The incremental costs and incremental QALYs in the base case analysis for each of the five strategies are summarised in Table 5.12. Taking nothing/placebo as the reference (least expensive) strategy, the other four strategies were shown to be more effective but were each associated with a very high ICER (all > £0.6 million/QALY) and were not considered to be cost-effective. Therefore at a willingness to pay (WTP) threshold of £20,000/QALY, nothing/placebo is the most cost-effective strategy. This conclusion was robust to structural sensitivity analysis and all one-way sensitivity analysis tested (Section A4.2),except for discounting the cost of PEG-G-CSF. At a WTP threshold of £20,000/QALY:

Table 5.12

Incremental costs and effectiveness by treatment strategy for solid tumour patients who can not take quinolone (baseline risk of neutropenic sepsis of one course of chemotherapy: 34.41%).

When the discount to the cost of PEG-G-CSF was over 73.85% (corresponding price: £179.5 per single subcutaneous injection (6mg), secondary prophylaxis with PEG-G-CSF became the most cost-effective strategy.
When the discount to the cost of PEG-G-CSF was over 84.13% (corresponding price: £108.9 per single subcutaneous injection (6mg), primary prophylaxis with PEG-G-CSF became the most cost-effective strategy.

Primary or secondary prophylaxis with G(M)-CSF is never the most cost-effective strategy for any of the three patient groups of interest, even when extreme scenarios were considered, for example: 100% risk of neutropenic sepsis per cycle of chemotherapy, 90% drug discount, reduced days of using G(M)-CSF (5-day per cycle of chemotherapy), reduced daily dose (one vial of G(M)-CSF for all adult patients regardless of weight) etc.

The result of the probabilistic sensitivity analysis shows that the probability of nothing/placebo becoming cost-effective is always 100%, at a willingness to pay between £10,000 to £40,000 per QALY.

Adult/elderly patients with non-Hodgkin lymphoma

For adult patients with non-Hodgkin lymphoma, no clinical evidence was identified for the use of quinolone alone for either primary or secondary prophylaxis therefore neither strategy was included in this analysis.

Compared to G(M)-CSF alone, G(M)-CSF + quinolone is more expensive and less effective in terms of preventing neutropenic sepsis so both primary and secondary prophylactic G(M)-CSF + quinolone strategies were excluded. As a result cost-effectiveness was only formally examined for the following five strategies:

Nothing/placebo
Primary prophylaxis with G(M)-CSF
Secondary prophylaxis with G(M)-CSF
Primary prophylaxis with PEG-G-CSF
Secondary prophylaxis with PEG-G-CSF

The incremental costs and incremental QALYs in the base case analysis for each of the five strategies are summarised in Table 5.13. Taking nothing/placebo as the reference (least expensive) strategy, the other four strategies were shown to be more effective, but were each associated with a very high ICER (all > £1.2 million/QALY) and were not considered to be cost effective. Therefore at a WTP threshold of £20,000/QALY, nothing/placebo is the most cost-effective strategy. This conclusion was robust to structural sensitivity analysis and all one-way sensitivity analysis tested (Section A4.2), except for discounting the cost of PEG-G-CSF. At a WTP threshold of £20,000/QALY:

Table 5.13

Incremental costs and effectiveness by treatment strategy for non-Hodgkin lymphoma patients (baseline risk of neutropenic sepsis of one course of chemotherapy: 44.22%).

When the discount to the cost of PEG-G-CSF was over 83.49% (corresponding price: £113.3 per single subcutaneous injection (6mg), secondary prophylaxis with PEG-G-CSF became the most cost-effective strategy.
When the discount to the cost of PEG-G-CSF was over 89.12% (corresponding price: £74.7 per single subcutaneous injection (6mg), primary prophylaxis with PEG-G-CSF became the most cost-effective strategy.

Primary or secondary prophylaxis with G(M)-CSF is never the most cost-effective strategy, even when extreme scenarios were considered, for example: 100% risk of neutropenic sepsis per cycle of chemotherapy, 90% drug discount of G(M)-CSF, reduced days of using G(M)-CSF (5-day per cycle of chemotherapy), reduced daily dose (one vial of G(M)-CSF for all adult patients regardless of weight) etc.

The result of probabilistic sensitivity analysis shows that the probability for nothing/placebo becoming cost-effective is always 100%, at a willingness to pay between £10,000 to £40,000 per QALY.

Adult/elderly patients with Hodgkin lymphoma

For adult/elderly patients with Hodgkin lymphoma, clinical evidence was only available for the use of G(M)-CSF for either primary or secondary prophylaxis. Therefore cost-effectiveness was only formally examined for the following three strategies:

Nothing/placebo
Primary prophylaxis with G(M)-CSF
Secondary prophylaxis with G(M)-CSF

The incremental costs and incremental QALYs in the base case analysis for each of the three strategies are summarised in Table 5.14. Taking nothing/placebo as the reference (least expensive) strategy, the other two strategies were shown to be more effective, but were each associated with a very high ICER (both > £18.2 million/QALY) and were therefore not considered to be cost effective. Therefore at a WTP threshold of £20,000/QALY, nothing/placebo is the most cost-effective strategy. This conclusion was robust to all one-way sensitivity analysis tested (Section A4.2).

Table 5.14

Incremental costs and effectiveness by treatment strategy for Hodgkin lymphoma patients (baseline risk of neutropenic sepsis of one course of chemotherapy: 20.27%).

Recommendations

For adult patients (aged 18 years and older) with acute leukaemias, stem cell transplants or solid tumours in whom significant neutropenia (neutrophil count 0.5 × 10⁹ per litre or lower) is an anticipated consequence of chemotherapy, offer prophylaxis with a fluoroquinolone during the expected period of neutropenia only
Rates of antibiotic resistance and infection patterns should be monitored in treatment facilities where patients are having fluoroquinolones for the prophylaxis of neutropenic sepsis¹⁶.
Do not routinely offer granulocyte-colony stimulating factor (G-CSF) for the prevention of neutropenic sepsis in adults receiving chemotherapy unless they are receiving G-CSF as an integral part of the chemotherapy regimen or in order to maintain dose intensity.

16: For more information see the Department of Health's Updated guidance on the diagnosis and reporting of Clostridium difficile and guidance from the Health Protection Agency and the Department of Health on Clostridium difficile infection: how to deal with the problem.

Linking Evidence to Recommendations

The aim of this topic was to identify if prophylactic treatment with antibiotics, growth factors and/or granulocyte infusion could improve short term outcomes in patients receiving anticancer treatment. This topic did not investigate the effect of G-CSF as an integral part of a chemotherapy regimen (for example, CHOP-14) or on dose intensity of chemotherapy.

The GDG assessed the clinical effectiveness of antibiotics, growth factors and granulocyte infusions in all patient groups. No evidence was found of a clinical benefit for granulocyte infusions and so cost-effectiveness analysis was undertaken only for growth factors and antibiotics. Because of the heterogeneity and complexity of anticancer treatment, formal cost-effectiveness analysis focused on the group of adult patients receiving outpatient treatment for solid tumours, Hodgkin lymphoma and non-Hodgkin lymphoma.

Studies of patients with stem cell transplants or leukaemia were excluded from the formal cost-effectiveness analysis because the GDG recognised that the costs of prophylaxis for inpatient-only management are very different from outpatient management. Paediatric patients were also excluded from the formal cost-effectiveness analysis because of considerable clinical heterogeneity in the treatment regimens, and a paucity of direct evidence which precluded building a meaningful model for analysis.

The GDG considered that the outcomes of death (short-term mortality), incidence of neutropenic sepsis, bacterial resistance, secondary infection, critical care, length of hospital stay and quality of life were the most clinically relevant. No evidence was reported for secondary infection, critical care or quality of life. Evidence was available for short-term mortality, bacterial resistance, and incidence of neutropenic sepsis. Overall the evidence for all outcomes was of ‘low’ quality with potential bias as assessed by GRADE.

The GDG noted that evidence directly comparing growth factors and antibiotics (ciprofloxacin and cotrimoxazole) was very sparse and of low quality. The GDG were surprised to find that the vast majority of evidence compared growth factors, predominately G-CSF, against no prophylaxis. The GDG also noted that there were very limited data available on the combination of growth factors with fluoroquinolones.

The GDG noted that the clinical evidence comparing antibiotics with placebo was of low quality and showed that antibiotics were effective at reducing overall short term mortality and incidence of neutropenic sepsis. The clinical evidence comparing growth factors against placebo was of low quality and showed no difference in effect on overall short term mortality.

However this evidence did show that growth factors reduce the incidence of neutropenic sepsis and they were also reported to shorten the length of hospital stay. The GDG considered that reduced overall short term mortality was the most important outcome.

Sparse evidence also reported antibiotic resistance with the use of prophylactic antibiotics. This demonstrated that whilst isolation of bacteria resistant to the prophylactic antibiotic may have increased there was still a reduction in overall mortality. The GDG recognised that prophylactic antibiotics contribute to antibiotic resistance but concluded that in patients receiving anticancer treatment the evidence suggests the benefits outweigh the risk.

Evidence was reported for both fluoroquinolones and cotrimoxazole as antibiotic prophylaxis. However the GDG chose to focus on the evidence related to fluoroquinolones because of concerns that changing anti-microbial resistance patterns meant the cotrimoxazole trials may no longer be applicable (Gafter-Gvili, et al., 2005). Consequently the GDG acknowledged that any recommendations made would only be able to focus on fluoroquinolones, because these studies were more recent include a large study undertaken in the UK population and would therefore more accurately reflect the current microbiological environment. The GDG were aware that this approach would exclude all evidence related to antibiotic prophylaxis with cotrimoxazole and that the smaller number of studies would decrease the precision in the estimates of effect, with the potential to increase uncertainty around any recommendation.

The GDG noted that international guidelines such as American Society of Clinical Oncology (Smith et al, 2006), The National Comprehensive Cancer Network (NCCN, 2011) and European Organisation for Research and Treatment of Cancer (Aapro, et al., 2010) recommend the use of G-CSF in selected patients who have a neutropenic sepsis risk of greater than 20%. The GDG also noted that these guidelines were based on the comparison of G-CSF with no prophylaxis, rather than with antibiotics, and did not assess the cost-effectiveness of their recommendations. In addition these guidelines had been developed in non UK healthcare settings.

The GDG considered the issue of paediatric patients carefully, balancing the potential benefits of extrapolating evidence from adult patients against the risks of adverse effects from the medications. Potential similarities between children undergoing stem cell transplantation and treatment for acute leukaemia in adults were considered, as were the documented differences between children and adults in the range of infecting organisms, underlying malignant diagnoses and treatment regimens. The GDG noted a large RCT was in progress by the Children's Oncology Group in North America addressing this question. They also noted the very different treatments used in treating the majority of children and young people with solid tumours compared to the majority of adult solid tumours. The GDG therefore concluded that there was too little evidence to recommend the use of either antibiotics or GCSF in this group, but identified this as an area for research.

The results of the cost-effectiveness analysis showed that for adult patients with solid tumours, primary prophylaxis with fluoroquinolones was more cost-effective than other strategies. This conclusion was robust to sensitivity analysis. For adult patients with solid tumours who cannot receive fluoroquinolones, no prophylaxis was shown to be the most cost-effective strategy. However, this result was shown to be sensitive to adjustments in several of the inputs to the model. As a result of this uncertainty the GDG did not feel able to make a recommendation for adult patients with solid tumours who cannot receive fluoroquinolones.

Little clinical evidence was found comparing fluoroquinolones with no prophylaxis for patients with lymphoma (Hodgkin or non-Hodgkin). Therefore the cost-effectiveness analysis only compared G-CSF or G-CSF + fluoroquinolone with no prophylaxis in these patients. The results showed that although G-CSF or G-CSF + fluoroquinolone could reduce the incidence of neutropenic sepsis; the ICER of both strategies was far above NICE'S £20,000 per QALY threshold and consequently the strategy of no prophylaxis was the most cost effective. However given that data were not available to compare all the strategies of interest the GDG was uncertain whether prophylaxis with antibiotics and/or G-CSF was clinically and cost-effective for lymphoma patients. They therefore decided not to make any recommendations on this issue.

Based on their clinical experience the GDG considered that for patients undergoing stem-cell transplantation and during intensive treatment for acute leukaemia the additional costs of antibiotic prophylaxis would be small and vastly outweighed by the improvement in short term mortality.

A systematic review of published economic evidence for this topic identified 10 papers that were relevant. However all papers had either very serious or potentially serious limitations. Therefore the GDG decided to use the results of the cost-effectiveness analysis conducted as part of this guideline to inform their recommendations.

The GDG considered that the benefits of recommending the use of fluoroquinolones in primary prophylaxis for this subset of patients would be fewer deaths and hospital admissions and potentially improved quality of life. The GDG noted that there are risks associated with recommending primary prophylaxis with fluoroquinolones, such as resistant bacterial infections and super-infection with Clostridium difficile and that monitoring for antimicrobial resistance should be carefully undertaken. However, the GDG noted, based on their clinical experience, that the death rate from such infections in this population is likely to be less than the death rate from neutropenic sepsis. The GDG also noted that the use of fluoroquinolones can have side effects, but agreed that the benefit of saving lives outweighed any potential harms.

The GDG noted the high ICER for G(M)-CSF in the prevention of neutropenic sepsis. Whilst the GDG acknowledged that clinicians in some settings are able to source G(M)-CSF products at substantially reduced prices, it was noted that these arrangements are fluid and regional, and therefore no national recommendations can be based on these costs. Not withstanding this, the GDG noted that the nursing costs of administering G(M)-CSF for preventing neutropenic sepsis result in this intervention not being cost effective, even at reduced prices.

One-way sensitivity analysis has shown that the economic model was sensitive to discounting the cost of PEG-G-CSF. PEG-G_CSF becomes cost-effective for secondary prophylaxis in patients with solid tumours who cannot take fluoroquinolones at less than £179.83 per single subcutaneous injection (6mg). However the GDG considered that is was unlikely that PEG-G-CSF would be available at these levels of discount. It was not possible to calculate similar thresholds for other patient groups because of a lack of clinical evidence (see Appendix A). These elements of uncertainty along with the high ICER described by the economic model led the GDG not to recommend the routine use of G(M)-CSF for the prevention of infectious complications and death from neutropenic sepsis. The GDG were aware that G(M)-CSF is an integral part of some chemotherapy regimens, or is used for maintaining dose intensity. Although this was outside the scope of this guideline and the evidence on this has not been reviewed, the GDG agreed that the use of G(M)-CSF for these indications should be acknowledged in the recommendation.

Based on the clinical evidence and the results of the cost-effectiveness analysis the GDG decided to recommend primary prophylaxis with fluoroquinolones for patients with acute leukaemias, stem cell transplants and adult patients with solid tumours during the period of expected neutropenia. They also recommended further research be undertaken in examining the cost-effectiveness of antibiotics and G-CSF in preventing neutropenic sepsis in children and young people. The GDG noted that in making a recommendation for primary prophylactic treatment a recommendation for secondary prophylactic treatment was no longer relevant. Because of the limited data available on the combination of growth factors with antibiotics, the GDG did not feel able to make any recommendations on this.

Research recommendation

Randomised studies should investigate primary prophylaxis of neutropenic sepsis in 2 populations: children and young people (aged under 18) having treatment for solid tumours or haematological malignancies, or stem cell transplantation; and adults (aged 18 and older) diagnosed with lymphoma. The studies should compare the effectiveness of fluoroquinolone antibiotics given alone, fluoroquinolone antibiotics given together with granulocyte-colony stimulating factor (G-CSF) preparations, and G-CSF preparations given alone. Outcome measures should include overall mortality, infectious episodes and adverse events. In addition, quality of life should be determined using quantitative and qualitative methods. The resulting data should be used to develop a cost-effectiveness analysis comparing these 3 forms of prophylaxis in children and young people having anticancer treatment, and in adults diagnosed with lymphoma.

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Footnotes

10: Converted from 2005 Netherlandish Euros using a PPP exchange rate of 0.78 then uprated by inflation factor of 109% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

11: Converted from 2002 Netherlandish Euros using a PPP exchange rate of 0.78 then uprated by inflation factor of 115% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

12: Converted from 2009 Canadian dollars using a PPP exchange rate of 0.55 then uprated by inflation factor of 106% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

13: In the economic analysis, it is assumed that the relative risk of a neutropenic sepsis event in the first cycle of chemotherapy compared with cycle two onwards is 3.69 (Cullen, 2007). Therefore by testing a range of 5-100% risk of neutropenic sepsis (per cycle) for Cycle 2 onwards; we tested a range of 1.4-100% risk of neutropenic sepsis (per cycle) for the first cycle of chemotherapy.

14: Average cost of filgrastim and lenograstim assuming that the daily dose of G(M)-CSF for all adult patients is one vial (one single 30 million-unit syringe of filgrastim or one single 33.6 million-unit syringe of lenograstim) regardless of patient weight.

15: Average cost of filgrastim and lenograstim, based on BNF recommended dose (500,000 units/kg daily) and patient weight distribution reported by: Green 2003, Romieu 2007, and Gigg 2003. The detailed calculation process is reported in Appendix A10

Publication Details

Copyright

Publisher

National Institute for Health and Clinical Excellence (NICE), London

NLM Citation

National Collaborating Centre for Cancer (UK). Neutropenic Sepsis: Prevention and Management of Neutropenic Sepsis in Cancer Patients. London: National Institute for Health and Clinical Excellence (NICE); 2012 Sep. (NICE Clinical Guidelines, No. 151.) 5, Reducing the risk of septic complications of anticancer treatment.

Clinical question: Does prophylactic treatment with growth factors, granulocyte infusion and/or antibiotics improve outcomes in patients at risk of neutropenic sepsis?

Table 5.1GRADE profile: Is primary prophylaxis with G(M)-CSF (with or without antibiotics) more effective than no primary prophylaxis with G(M)-CSF (with or without antibiotics) at improving outcomes in patients at risk of neutropenic sepsis

Quality assessment							No of patients		Effect		Quality
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	G(M)-CSF	No G(M)-CSF	Relative (95% CI)	Absolute	Quality
Mortality
80	randomised trials	no serious risk of bias¹	no serious inconsistency	no serious indirectness	no serious imprecision	None	465/6146 (7.6%)	472/5913 (8%)	RR 0.95 (0.84 to 1.08)	4 fewer per 1000 (from 13 fewer to 6 more)	HIGH
Mortality (paediatric patients)
7	randomised trials	serious²	no serious inconsistency	no serious indirectness	very serious³	None	6/301 (2%)	4/303 (1.3%)	RR 1.46 (0.42 to 5.11)	6 more per 1000 (from 8 fewer to 54 more)	VERY LOW
Mortality (adult patients)
34	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	serious⁵	None	105/1986 (5.3%)	117/1780 (6.6%)	RR 0.85 (0.66 to 1.11)	10 fewer per 1000 (from 22 fewer to 7 more)	LOW
Mortality (elderly patients)
8	randomised trials	no serious risk of bias¹	no serious inconsistency	no serious indirectness	no serious imprecision	None	311/3778 (8.2%)	317/3586 (8.8%)	RR 1.04 (0.87 to 1.24)	4 more per 1000 (from 11 fewer to 21 more)	HIGH
Mortality (prophylactic antibiotics used)
15	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious⁵	None	51/1045 (4.9%)	59/1056 (5.6%)	RR 0.92 (0.64 to 1.32)	4 fewer per 1000 (from 20 fewer to 18 more)	MODERATE
Mortality (prophylactic antibiotics not mandated)
66	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	414/5101 (8.1%)	413/4857 (8.5%)	RR 0.96 (0.84 to 1.09)	3 fewer per 1000 (from 14 fewer to 8 more)	HIGH
Mortality (leukaemia studies)
30	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision⁵	None	263/2725 (9.7%)	277/2597 (10.7%)	RR 0.95 (0.81 to 1.12)	5 fewer per 1000 (from 20 fewer to 13 more)	HIGH
Mortality (lymphoma or solid tumour studies)
27	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious⁵	None	109/2204 (4.9%)	113/2155 (5.2%)	RR 0.91 (0.64 to 1.28)	5 fewer per 1000 (from 19 fewer to 15 more)	MODERATE
Mortality (stem cell transplant studies)
21	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious⁵	None	93/1098 (8.5%)	79/1044 (7.6%)	RR 1.02 (0.77 to 1.34)	2 more per 1000 (from 17 fewer to 26 more)	MODERATE
Mortality (G-CSF studies)
46	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	None	267/3726 (7.2%)	265/3531 (7.5%)	RR 0.98 (0.83 to 1.15)	2 fewer per 1000 (from 13 fewer to 11 more)	HIGH
Mortality (GM-CSF studies)
34	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	None	193/1957 (9.9%)	193/1917 (10.1%)	RR 0.95 (0.84 to 1.08)	5 fewer per 1000 (from 16 fewer to 8 more)	HIGH
Infection related mortality
67	randomised trials	no serious risk of bias¹^,⁶	no serious inconsistency	no serious indirectness	serious⁵^,⁷	none	150/4901 (3.1%)	179/4673 (3.8%)	RR 0.82 (0.66 to 1.02)	7 fewer per 1000 (from 13 fewer to 1 more)	MODERATE
Infection related mortality (prophylactic antibiotics used)
14	randomised trials	serious⁸	no serious inconsistency	no serious indirectness	Serious⁵	None	18/1177 (1.5%)	42/1181 (3.6%)	RR 0.47 (0.28 to 0.8)	19 fewer per 1000 (from 7 fewer to 26 fewer)	LOW
Infection related mortality (prophylactic antibiotics not mandated)
53	randomised trials	serious⁹	no serious inconsistency	no serious indirectness	no serious imprecision	None	132/3724 (3.5%)	137/3492 (3.9%)	RR 0.91 (0.72 to 1.16)	4 fewer per 1000 (from 11 fewer to 6 more)	MODERATE
Febrile neutropenia
49	randomised trials	serious¹⁰	no serious inconsistency	no serious indirectness	no serious imprecision	None	1293/4529 (28.5%)	1649/4470 (36.9%)	RR 0.71 (0.63 to 0.8)	107 fewer per 1000 (from 74 fewer to 136 fewer)	MODERATE
Febrile neutropenia (leukaemia studies)
10	randomised trials	serious	no serious inconsistency	no serious indirectness	no serious imprecision	None	389/867 (44.9%)	339/808 (42%)	RR 0.81 (0.66 to 0.99)	80 fewer per 1000 (from 4 fewer to 143 fewer)	MODERATE
Febrile neutropenia (lymphoma or solid tumour studies)
32	randomised trials	serious⁹	no serious inconsistency	no serious indirectness	no serious imprecision	None	730/3381 (21.6%)	1070/3412 (31.4%)	RR 0.64 (0.53 to 0.76)	113 fewer per 1000 (from 75 fewer to 147 fewer)	MODERATE
Febrile neutropenia (stem cell transplant studies)
3	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious⁵	none	135/193 (69.9%)	127/172 (73.8%)	RR 0.94 (0.74 to 1.2)	44 fewer per 1000 (from 192 fewer to 148 more)	MODERATE
Documented infection
60	randomised trials	serious⁹	no serious inconsistency	no serious indirectness	no serious imprecision	None	1874/5921 (31.7%)	2043/5704 (35.8%)	Rate ratio 0.85 (0.79 to 0.92)	54 fewer per 1000 (from 29 fewer to 75 fewer)	MODERATE
Resistance to the antibiotic used for prophylaxis - not reported
0	-	-	-	-	-	None	-	-	-	-
Length of hospital stay (Better indicated by lower values)
43	randomised trials	no serious risk of bias¹¹	no serious inconsistency	serious indirectness¹²	no serious imprecision	None	0	-	-	Mean difference 2.41 days less with G(M)-CSF (3.13 to 1.7 lower)	MODERATE
Quality of life - not reported
0	-	-	-	-	-	None	-	-	-	-

1: This review included 80 trials: 26/80 trials had adequate allocation concealment and 35/80 had double blinding. Sensitivity analyses according to allocation concealment and double blinding, did not show a significant effect of CSF treatment on mortality, infectious mortality or febrile neutropenia.

2: None of the 7 paediatric mortality studies had adequate allocation concealment, 2/7 had double blinding

3: Low number of events

4: 11/34 adult mortality studies had adequate allocation concealment, 15/34 had double blinding.

5: Low number of events

6: 67 trials reported infection related mortality: 19/67 had adequate allocation concealment and 29/67 had double blinding.

7: The confidence interval for the pooled estimate spans both no effect and significant benefit.

8: 2/14 trials had adequate allocation concealment, 4/14 double blinding.

9: Most of the trials did not have adequate allocation concealment or double blinding

10: Of the studies reporting febrile neutropenia 9/49 had adequate allocation concealment and 15/49 had double blinding.

11: The quality of studies of duration of hospital stay was not reported.

12: Hospital discharge criteria in these studies were likely to incorporate neutrophil count and thus influenced by the use of colony stimulating factors.

Table 5.2GRADE profile: Is primary prophylaxis with G(M)-CSF plus antibiotics more effective than primary prophylaxis with antibiotics at improving outcomes for patients at risk of neutropenic sepsis

Quality assessment							No of patients		Effect		Quality
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	G(M)-CSF+ABX	Antibiotics alone	Relative (95% CI)	Absolute	Quality
Febrile neutropenia (quinolone studies) – one trial in patients with solid tumours and one in non-Hodgkin lymphoma
2	randomised trials	serious¹	serious⁶	no serious indirectness	serious²	none	53/432 (12.3%)	71/410 (17.3%)	RR 0.703 (0.414 to 1.193)	51 fewer per 1000 (from 101 fewer to 33 more)	VERY LOW
Mortality from any cause (quinolone studies) – one trial each in patients with solid tumours , non-Hodgkin lymphoma, leukaemia and stem cell transplant
4	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious²	none	25/408 (6.1%)	33/401 (8.2%)	RR 0.817 (0.491 to 1.36)	15 fewer per 1000 (from 42 fewer to 30 more)	MODERATE
Infectious mortality (quinolone studies) – one trial each in patients with non-Hodgkin lymphoma, leukaemia and stem cell transplant; two in patients with solid tumours
5	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious²	none	13/498 (2.6%)	29/486 (6%)	RR 0.478 (0.254 to 0.898)	31 fewer per 1000 (from 6 fewer to 45 fewer)	MODERATE
Febrile neutropenia (cotrimoxazole studies) – five leukaemia, two non-Hodgkin and two stem cell transplant trials
9	randomised trials	serious³	no serious inconsistency	no serious indirectness	no serious imprecision	none	349/504 (69.2%)	372/483 (77%)	RR 0.928 (0.86 to 1.002)	55 fewer per 1000 (from 108 fewer to 2 more)	MODERATE
Mortality from any cause (cotrimoxazole studies) – five leukaemia, two non-Hodgkin and four stem cell transplant trials
11	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	serious²	none	32/706 (4.5%)	29/705 (4.1%)	RR 1.102 (0.685 to 1.773)	4 more per 1000 (from 13 fewer to 32 more)	LOW
Infectious mortality (cotrimoxazole studies) – four leukaemia, three non-Hodgkin and two stem cell transplant trials
9	randomised trials	serious⁵	no serious inconsistency	no serious indirectness	serious²	none	7/731 (0.96%)	14/728 (1.9%)	RR 0.6 (0.264 to 1.367)	8 fewer per 1000 (from 14 fewer to 7 more)	LOW
Length of Hospital stay – not reported
0	-	-	-	-	-	none	-	-	-	-
Quality of life - not reported
0	-	-	-	-	-	none	-	-	-	-

1: 1/2 double blind, 0/2 adequate allocation concealment

2: Low number of events

3: 1/9 had adequate allocation concealment, 2/9 double blinding

4: 1/11 had adequate allocation concealment, 2/11 double blinding

5: 0/9 had adequate allocation concealment, 1/9 was double blind

6: Significant heterogeneity (I²=67%)

Table 5.3GRADE profile: Is primary prophylaxis with antibiotics more effective than no primary prophylaxis at improving outcomes in patients at risk of neutropenic sepsis

Quality assessment							No of patients		Effect		Quality
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Antibiotics	No primary prophylaxis	Relative (95% CI)	Absolute	Quality
Mortality (quinolone studies)
10	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious²	none	32/1295 (2.5%)	57/1286 (4.4%)	RR 0.615 (0.4 to 0.946)	17 fewer per 1000 (from 2 fewer to 27 fewer)	MODERATE
Infection related mortality (quinolone studies)
6	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	very serious²^,³	none	19/1295 (1.5%)	36/1286 (2.8%)	RR 0.58 (0.336 to 1.001)	12 fewer per 1000 (from 19 fewer to 0 more)	LOW
Febrile neutropenia (quinolone studies)
10	randomised trials	serious¹^,⁴	serious⁵	no serious indirectness	no serious imprecision	none	419/1339 (31.3%)	594/1341 (44.3%)	RR 0.727 (0.62 to 0.852)	121 fewer per 1000 (from 66 fewer to 168 fewer)	LOW
Febrile neutropenia (ciprofloxacin studies)
2	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	very serious²^,⁶	none	19/56 (33.9%)	26/56 (46.4%)	RR 0.95 (0.66 to 1.35)	23 fewer per 1000 (from 158 fewer to 163 more)	LOW
Febrile neutropenia (levofloxacin studies)
3	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	347/1160 (29.9%)	460/1160 (39.7%)	RR 0.76 (0.7 to 0.82)	95 fewer per 1000 (from 71 fewer to 119 fewer)	HIGH
Febrile neutropenia (ofloxacin studies)
4	randomised trials	no serious risk of bias	serious⁵	no serious indirectness	serious²^,⁶	none	34/111 (30.6%)	70/106 (66%)	RR 0.35 (0.1 to 1.23)	429 fewer per 1000 (from 594 fewer to 152 more)	LOW
Febrile neutropenia (TMP-SMZ studies)
16	randomised trials	no serious risk of bias	serious⁵	no serious indirectness	no serious imprecision	none	367/713 (51.5%)	473/711 (66.5%)	RR 0.80 (0.69 to 0.92)	133 fewer per 1000 (from 53 fewer to 206 fewer)	MODERATE
Infection with bacteria resistant to the antibiotic used for prophylaxis
15	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious²	none	74/1680 (4.4%)	50/1654 (3%)	RR 1.43 (1 to 2.03)	13 more per 1000 (from 0 more to 31 more)	MODERATE
Infection with bacteria resistant to quinolones (quinolone studies)
4	randomised trials	no serious risk of bias	serious inconsistency⁵	no serious indirectness	serious²	none	44/1185 (3.7%)	39/1180 (3.3%)	RR 0.87 (0.18 to 4.15)	4 fewer per 1000 (from 27 fewer to 104 more)	LOW
Colonisation with bacteria resistant to quinolones (quinolone studies)
2	randomised trials	serious risk of bias⁷	no serious inconsistency	no serious indirectness	serious²	none	6/47 (12.8%)	2/46 (4.3%)	RR 3.30 (1.03 to 12.56	113 more per 1000 (from 1 more to 503 more)	LOW
Length of hospital stay - not reported
0	-	-	-	-	-	none	-	-	-	-
Quality of life - not reported
0	-	-	-	-	-	none	-	-	-	-

1: Most studies did not have clear allocation concealment or double blinding.

2: Low number of events.

3: Confidence interval of the pooled estimate crosses both no effect and significant benefit.

4: 9/25 had adequate allocation concealment and 13/25 double blinding

5: Statistically significant heterogeneity

6: 95% confidence interval around the pooled estimate of effect includes both no effect and appreciable benefit or appreciable harm.

7: Both trials had unclear allocation concealment

Table 5.4GRADE profile: Is primary prophylaxis with quinolone more effective than primary prophylaxis with cotrimoxazole at improving outcomes in patients at risk of neutropenic sepsis

Quality assessment							No of patients		Effect		Quality
No of studies	Design	Limitations	Inconsistency	Indirectness	Imprecision	Other considerations	Ciprofloxacin, levofloxacin or ofloxacin	Cotrimoxazole	Relative (95% CI)	Absolute	Quality
Mortality
6	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²^,³	none	26/372 (7%)	17/317 (5.4%)	RR 1.24 (0.57 to 2.67)	13 more per 1000 (from 23 fewer to 90 more)	LOW
Febrile neutropenia (ciprofloxacin vs TMP-SMZ studies)
3	randomised trials	serious⁴	no serious inconsistency	no serious indirectness	serious²^,³	none	161/219 (73.5%)	143/212 (67.5%)	RR 1.34 (0.88 to 2.04)	229 more per 1000 (from 81 fewer to 702 more)	LOW
Febrile neutropenia (levofloxacin vs TMP-SMZ studies) - not reported
0	-	-	-	-	-	none	-	-	-	-
Febrile neutropenia (ofloxacin vs TMP-SMZ studies)
3	randomised trials	serious⁵	no serious inconsistency	no serious indirectness	serious²	none	65/142 (45.8%)	84/131 (64.1%)	RR 0.39 (0.23 to 0.67)	391 fewer per 1000 (from 212 fewer to 494 fewer)	LOW
Colonisation with bacteria resistant to the antibiotic used for prophylaxis
2	randomised trials	serious⁶	no serious inconsistency	no serious indirectness	serious²	none	39/98 (39.8%)	58/86 (67.4%)	RR 0.58 (0.44 to 76)	283 fewer per 1000 (from 378 fewer to 1000 more)	LOW
Infection with bacteria resistant to the antibiotic used for prophylaxis
3	randomised trials	serious⁶	no serious inconsistency	no serious indirectness	very serious⁷	none	3/100 (3%)	6/100 (6%)	RR 0.24 (0.08 to 0.77)	46 fewer per 1000 (from 14 fewer to 55 fewer)	VERY LOW
Quality of life - not reported
0	-	-	-	-	-	none	-	-	-	-
Length of hospital stay - not reported
0	-	-	-	-	-	none	-	-	-	-

1: 1/6 trials had adequate allocation concealment, 1/6 had double blinding

2: Low number of events

3: 95% confidence interval around the pooled estimate of effect includes both no effect and appreciable benefit or appreciable harm.

4: 1/3 had adequate allocation concealment, 1/3 had double blinding

5: No allocation concealment or blinding

6: 1 trial had adequate allocation concealment, none had double blinding

7: Very low number of events

Table 5.5GRADE profile: Is primary prophylaxis with G(M)-CSF more effective than primary prophylaxis with antibiotics at improving outcomes for patients at risk of neutropenic sepsis

Quality assessment							No of patients		Effect		Quality
No of studies	Design	Limitations	Inconsistency	Indirectness	Imprecision	Other considerations	G-CSF	Antibiotics	Relative (95% CI)	Absolute	Quality
Mortality
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious²^,³	none	7/78 (9%)	5/77 (6.5%)	RR 1.42 (0.43 to 4.68)	27 more per 1000 (from 37 fewer to 239 more)	VERY LOW
Febrile neutropenia
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious²^,³	none	7/18 (38.9%)	7/22 (31.8%)	RR 1.22 (0.53 to 2.84)	70 more per 1000 (from 150 fewer to 585 more)	VERY LOW
Quality of life - not reported
0	-	-	-	-	-	none	-	-	-	-
Antibiotic resistance - not reported
0	-	-	-	-	-	none	-	-	-	-
Length of hospital stay (Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	Median 6 days (range 5 to 9)	Median 7 days (range 5 to 10)	-	median 1 day less with G-CSF	LOW

1: No blinding or unclear allocation concealment

2: Very low number of events

3: 95% confidence interval around the pooled estimate of effect includes both no effect and appreciable benefit or appreciable harm

Table 5.6GRADE profile: Is primary prophylaxis with pegfilgrastim more effective than primary prophylaxis with filgrastim at improving outcomes for patients at risk of neutropenic sepsis

Quality assessment							No of patients		Effect		Quality
No of studies	Design	Limitations	Inconsistency	Indirectness	Imprecision	Other considerations	Pegfilgrastim	Filgrastim	Relative (95% CI)	Absolute	Quality
Mortality - not reported
0	-	-	-	-	-	none	-	-	-	-
Febrile neutropenia
5	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²^,³	none	35/315 (11.1%)	51/291 (17.5%)	RR 0.66 (0.44 to 0.98)	60 fewer per 1000 (from 4 fewer to 98 fewer)	LOW
Antibiotic resistance - not reported
0	-	-	-	-	-	none	-	-	-	-
length of hospital stay - not reported
0	-	-	-	-	-	none	-	-	-	-
Quality of life - not reported
0	-	-	-	-	-	none	-	-	-	-

1: 2/5 trials had double blinding, 2/5 were open label. 3/5 trials were phase II studies

2: Low number of events

3: 95% confidence interval around the pooled estimate of effect includes both no effect and appreciable benefit or appreciable harm.

Table 5.7GRADE profile: Is primary prophylaxis with granulocyte infusion more effective than no such prophylaxis at improving outcomes in patients at risk of neutropenic sepsis

Quality assessment							No of patients		Effect		Quality
No of studies	Design	Limitations	Inconsistency	Indirectness	Imprecision	Other considerations	Prophylaxis with granulocyte infusion	No prophylaxis with granulocyte infusion	Relative (95% CI)	Absolute	Quality
Mortality
10	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²^,³	none	62/347 (17.9%)	64/358 (17.9%)	RR 0.94 (0.71 to 1.25)	11 fewer per 1000 (from 52 fewer to 45 more)	LOW
Febrile neutropenia
2	randomised trials	serious⁴	serious⁵	no serious indirectness	serious²	none	46/66 (69.7%)	92/109 (84.4%)	RR 0.85 (0.69 to 1.05)	127 fewer per 1000 (from 262 fewer to 42 more)	VERY LOW
Antibiotic resistance - not reported
0	-	-	-	-	-	-	-	-	-	-
Length of hospital stay - not reported
0	-	-	-	-	-	-	-	-	-	-
Quality of life - not reported
0	-	-	-	-	-	-	-	-	-	-

1: One trial had adequate allocation concealment, blinding was unclear in all trials

2: Low number of events

3: 95% confidence interval around the pooled estimate of effect includes both no effect and appreciable benefit or appreciable harm.

4: Unclear allocation concealment and blinding

5: Unexplained statistically significant heterogeneity

Table 5.8GRADE profile: Is secondary prophylaxis with G(M)-CSF more effective than no secondary prophylaxis at improving outcomes in patients with a prior episode of neutropenic sepsis

Quality assessment							No of patients		Effect		Quality
No of studies	Design	Limitations	Inconsistency	Indirectness	Imprecision	Other considerations	Secondary prophylaxis with G(M)-CSF	No secondary prophylaxis	Relative (95% CI)	Absolute	Quality
Neutropenic events
1	randomised trials	no serious limitations	no serious inconsistency	serious¹	serious²	none	36/204 (17.6%)	132/203 (65%)	RR 0.27 (0.2 to 0.37)	475 fewer per 1000 (from 410 fewer to 520 fewer)	LOW
Overtreatment, death, critical care, length of stay, duration of fever, quality of life - not reported
0	-	-	-	-	-	none	-	-	-	-

1: Neutropenic events were defined as ANC <1.0 ×10^˄9/l or neutropenic fever: thus were indirectly related to neutropenic sepsis.

2: Low number of events

Table 5.9GRADE profile: Is secondary prophylaxis with quinolone plus G-CSF more effective than secondary prophylaxis with G-CSF alone at improving outcomes in patients with a prior episode of neutropenic sepsis

Quality assessment							No of patients		Effect		Quality
No of studies	Design	Limitations	Inconsistency	Indirectness	Imprecision	Other considerations	Antibiotics plus G-CSF	G-CSF alone	Relative (95% CI)	Absolute	Quality
Documented infection
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²^,³	none	6/44 (13.6%)	15/48 (31.3%)	RR 0.44 (0.19 to 1.02)	175 fewer per 1000 (from 253 fewer to 6 more)	LOW
Overtreatment, death, critical care, length of stay, duration of fever, quality of life (Copy) - not reported
0	-	-	-	-	-	none	-	-	-	-

1: Unclear allocation concealment, no blinding mentioned.

2: Low number of events

3: 95% C.I. includes both no-effect and appreciable benefit

Table 5.10Modified GRADE profile: Cost effectivness of primary and secondary prophylaxis

Quality assessment			Summary of findings
Study	Limitations	Applicability	Population	Intervention	Comparator	Incremental cost (2010 £)	Incremental effects	ICER	Uncertainty
Borget, et al., 2009	Very serious limitations¹	Partially applicable²	A theoretical cohort of women with breast cancer. The base case is a 45-year-old woman with stage II breast cancer receiving four cycles of chemotherapy with a ≥20% risk of febrile neutropenia (FN).	Primary filgrastim (11-day)	Primary PEG-G-CSF	£1282.78³	<0 QALYs	Dominated	Results were also robust to changes in model inputs.
Borget, et al., 2009	Very serious limitations¹	Partially applicable²		Primary filgrastim (6-day)	Primary PEG-G-CSF	- £506.69³	-0.106 QALYs	£4770.00 per QALY gained³	Results were also robust to changes in model inputs.
Danova, et al., 2008	Very serious limitations⁴	Partially applicable⁵	A hypothetical cohort of 45-year-old women with stage II breast cancer receiving 4 cycles of chemotherapy associated with a ≥20% risk of FN.	Primary PEG-G-CSF	Primary filgrastim (6-day)	£36.70⁶	0.10 QALYs	£349.86 per QALY gained⁶	One-way and two-way sensitivity analysis was conducted but range of ICER was not reported. The paper only reported when the highest PEG-G-CSF and the lowest filgrastim price were used, ICER is still below per £43,522⁶ QALY.
Lathia, et al., 2009	Potentially serious limitations⁷	Partially applicable⁸	Patients with diffuse large B-cell lymphoma (the most common subtype of non-Hodgkin Lymphoma) receiving induction chemotherapy. Base-case analysis considered a cohort of 64-year-old men and women	Primary filgrastim (did not report if it is 6 or 11 days)	Nothing	£1992.48⁹	0.002 QALYs	£0.99 million per QALY gained⁹	All one-way sensitivity analysis yielded ICERs of greater than £0.58 million⁹ per QALY gained.
Lathia, et al., 2009	Potentially serious limitations⁷	Partially applicable⁸		Primary PEG-G-CSF	Nothing	£5765.08⁹	0.004 QALYs	£2.52million per QALY gained
Liu, et al., 2009	Very serious limitations¹⁰	Partially applicable¹¹	Women aged 30-80 years with early stage (I-III) breast cancer	Primary PEG-G-CSF	Primary filgrastim (6-day)	£505.54¹²	0.052 QALYs depends on scenarios	£ 9773.87 per QALY gained¹²	When the relative risk of FN was ≤1.3 for 6-day filgrastim versus pegfilgastim, the ICER exceeded
Liu, et al., 2009	Very serious limitations¹⁰	Partially applicable¹¹		Primary filgrastim (11-day)	Primary PEG-G-CSF	£ 1046.63¹²	-0.028 QALYs depends on scenarios	Dominated
Lyman, 2009 (a)	Very serious limitations ¹³	Partially applicable ¹⁴	A hypothetical cohort of patients with intermediate- or high-grade non-Hodgkin lymphoma receiving myelosuppressive chemotherapy (e.g, CHOP-21) with an FN risk of approximately ≥20%. A 65-year-old was chosen as base line.	Primary PEG-G-CSF	Primary filgrastim (6-day)	£192.96¹⁵	Range: 0.042-0.155 QALYs (depends on scenarios)	Range: £1244.61-4594.00 15 per QALY gained (depends on scenarios)	The probability for PEG-G-CSF to become more cost-effective over filgrastim was 50% with the threshold of £11132.47¹⁵ per QALY gained, 80% for £22,264.94¹⁵ per QALY gained, and 91% for £37,108.23¹⁵ per QALY gained.
Lyman, 2009 (b)	Very serious limitations ¹⁶	Partially applicable ¹⁷	Women 30-80 years with early stage (I to III) breast cancers who were receiving adjuvant myelosuppressive chemotherapy and had an FN risk of ≥20%.	Primary filgrastim (6-day)	Primary PEG-G-CSF	-£ 1005.63¹⁸	Range: -(0.043-0.094) QALYs depends on scenarios	Range: -£(10698.30-23386.35) 18 per QALY gained	Probabilistic sensitivity analysis show that the probability that strategy A is cost-effective compared with B was 50% for a threshold value of £14,843.29¹⁸ per QALY gained, 80% for a threshold value of £22,264.94¹⁸ per QALY gained, and 90% for a threshold value of £29,686.58¹⁸ per QALY gained.
Lyman, 2009 (b)	Very serious limitations ¹⁶	Partially applicable ¹⁷		Primary filgrastim (11-day)	Primary PEG-G-CSF	-£ 4899.77¹⁸	-(0.022-0.050) QALYs depends on scenarios	Dominated
Ramsey, 2009	Very serious limitations¹⁹	Partially applicable²⁰	Women aged 30 to 80 years with early stage (I to III) breast cancer receiving myelosuppressive chemotherapy with an FN risk of approximately 20%. The reference patient was 49 years old with stage II breast cancer receiving six cycles of chemotherapy.	Primary PEG-G-CSF	Secondary PEG-G-CSF	£6459.06²¹	0.076 QALYs	£86091.09²¹ per QALY gained	One-way: when FN case fatality was less than 2%, the ICER exceeded £148,432.9²¹ per QALY gained. The probability that pegfilgastim primary prophylaxis would be considered cost-effective at the threshold value compared with secondary prophylaxis was 12% for a WTP of £37,108.23²¹ per QALY gained, 40% of a WTP of £74,216.46 ²¹ per QALY gained, and 75% for a WTP of £148,432.92²¹ per QALY gained.
Timmer-Bonte, et al., 2008	Potentially serious limitations²²	Partially applicable²³	Patients with small cell lung cancer at risk of FN defined as 60 years of age or older, extensive disease, a Karnofsky performance stats of 40% to 70%, and/or having received prior chemotherapy. Patients have received primary prophylaxis with antibiotics or with antibiotics plus G(M)-CSF.	Secondary antibiotics + G(M)-CSF	Secondary antibiotics	£4970.03²⁴	0.02 FN-free cycle	£0.29 million ²⁴ per FN free cycle	Result is robust to probability of FN and treatment cost of FN (although when using higher FN-related costs, the strategies are less distinct in their monetary effects, but still favour antibiotics).
Timmer-Bonte, et al., 2008	Potentially serious limitations²²	Partially applicable²³		Secondary sequential approach (Antibiotics after the first episode of FN and antibiotics plus G(M)-CSF after another episode of FN.)	Secondary antibiotics	£1839.87²⁴	-0.11 FN-free cycle	Dominated
Timmer-Bonte, et al., 2006	Potentially serious limitations ²⁵	Partially applicable ²⁶	Small-cell lung cancer patients receiving standard dose chemotherapy.	Primary antibiotics + G(M)-CSF	Primary antibiotics	First cycle: £611.78²⁷ Entire treatment period: £4609.04²⁷	First cycle: 14% decrease of the probability of FN Entire treatment period: 23% decrease of the probability of FN	First cycle: £44.98²⁷ per percent decrease of the probability of FN Entire treatment: £329.28²⁷per percent decrease of the probability of FN	Sensitivity analysis has only been conducted for cycle 1. G(M)-CSF is cost saving if the probability of FN is more than 84%, the price of prophylactic G(M)-CSF is less than £421.95²⁷ per patient, or the cost of an episode of FN amount to greater than £10,366.07²⁷. The acceptability for the willingness to pay was approximately 50%.
Whyte, et al., 2011	Very serious limitations²⁸	Partially applicable²⁹	The base case consisted of a cohort of 52-year-old female patients diagnosed with stage II breast cancer in line with data on presenting characteristics.	Secondary lenograstim (11 days)	Nothing	£968	0.023 QALYs	Dominated	Results are highly sensitive to baseline FN risk. When willingness to pay is £20,000 per QALY, for a patient with a FN risk level of 11% -37%, secondary PEG-G-CSF is most cost-effective; for patients with a higher risk level, primary PEG-G-CSF is the most cost-effective. Using a WTP threshold of £30,000, primary prophylaxis with PEG-G-CSF was cost-effective for baseline FN risks greater than 29%.
				Secondary lenograstim (6 days)	Nothing	£462	0.023 QALYs	Dominated
				Secondary filgrastim (11 days)	Nothing	£852	0.024 QALYs	Dominated
				Secondary filgrastim (6 days)	Nothing	£397	0.024 QALYs	Dominated
				Secondary PEG-G-CSF	Nothing	If baseline risk =24%: £274 If baseline risk =31%:£253	If baseline risk =24%: 0.042 QALYs If baseline risk =31%: 0.069 QALYs	If baseline risk =24%: £6,500 per QALY gained If baseline risk =31%: £3,651 per QALY gained
				Primary lenograstim (11 days)	Nothing	£8326	0.075 QALYs	Dominated
				Primary lenograstim (6 days)	Nothing	£4355	0.075 QALYs	Dominated
				Primary filgrastim (11 days)	Nothing	£7434	0.077 QALYs	Dominated
				Primary filgrastim (6 days)	Nothing	£3865	0.077 QALYs	Dominated
				Primary PEG-G-CSF	Nothing	If baseline risk =24%: £3559 If baseline risk =31%:£3252	If baseline risk =24%: 0.128 QALYs If baseline risk =31%:0.181 QALYs	If baseline risk =24%: £38,482 per QALY gained If baseline risk =31%: £26,824 per QALY gained

1: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF; however it only counts the cost of G(M)-CSF without counting cost of chemotherapy. Not all estimates of input data come from the best available source (systematic review). Have conflicts of interest.

2: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF, not just G(M)-CSF. This study doesn't look at all interventions of interest. Health effects are not discounted at an annual rate of 3.5%.

3: Uprated from 2006 British Pounds using inflation factor of 115% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

4: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF; however it only counts the cost of G(M)-CSF without counting cost of chemotherapy. Have conflicts of interest.

5: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF, not just G(M)-CSF. This study is conducted in Italy, not in the UK. Doesn't look at all interventions of interest.

6: Converted from 2008 Italian Euros using a PPP exchange rate of 0.78 then uprated by inflation factor of 105% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

7: Only the abstract of this study has been published at the moment, so it is unclear whether all input data of this study come from the best available source.

8: This study is conducted in Canada, not in the UK. Doesn't look at all interventions of interest.

9: Converted from 2009 Canadian dollars using a PPP exchange rate of 0.55 then uprated by inflation factor of 106% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

10: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF; however it only counts the cost of G(M)-CSF without counting cost of chemotherapy. No costs were modelled beyond 1 year; while on the other hand, the effectiveness was modelled for lifetime. Have conflicts of interest.

11: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF, not just G(M)-CSF. This study doesn't look at all interventions of interest.

12: Uprated from 2006 British Pounds using inflation factor of 115% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

13: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF; however it only counts the cost of G(M)-CSF without counting cost of chemotherapy. Not all estimates of input data come from the best available source (systematic review). Have conflicts of interest.

14: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF, not just G(M)-CSF. This study is conducted in the U.S.A, not in the UK. Doesn't look at all interventions of interest.

15: Converted from 2006 U.S.A dollars using a PPP exchange rate of 0.69 then uprated by inflation factor of 108% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

16: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF; however it only counts the cost of G(M)-CSF without counting cost of chemotherapy. Not all estimates of input data come from the best available source (systematic review). Have conflicts of interest.

17: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF, not just G(M)-CSF. This study is conducted in the U.S.A, not in the UK. Doesn't look at all interventions of interest.

18: Converted from 2006 U.S.A dollars using a PPP exchange rate of 0.69 then uprated by inflation factor of 108% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

19: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF; however it only counts the cost of G(M)-CSF without counting cost of chemotherapy. Not all estimates of input data come from the best available source (systematic review). Have conflicts of interest.

20: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF, not just G(M)-CSF. This study is conducted in the U.S.A, not in the UK. Doesn't look at all interventions of interest.

21: Converted from 2006 U.S.A dollars using a PPP exchange rate of 0.69 then uprated by inflation factor of 108% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

22: Not all estimates of input data come from the best available source (systematic review).

23: This study is conducted in the Netherlands, not in the UK. Doesn't look at all interventions of interest. The value of health effects is not expressed in terms of quality-adjusted life years (QALYs).

24: Converted from 2005 Netherlandish Euros using a PPP exchange rate of 0.78 then uprated by inflation factor of 109% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

25: Not all estimates of input data come from the best available source (systematic review).

26: This study is conducted in the Netherlands, not in the UK. Doesn't look at all interventions of interest. The value of health effects is not expressed in terms of quality-adjusted life years (QALYs).

27: Converted from 2002 Netherlandish Euros using a PPP exchange rate of 0.78 then uprated by inflation factor of 115% (http://eppi.ioe.ac.uk/costconversion/default.aspx).

28: Whyte et al 2011 modelled three functions of G-CSF: 1). Reducing incidence of febrile neutropenia. 2). Reducing short-term mortality (by preventing febrile neutropenia). 3). Reducing long-term mortality (by maintaining chemotherapy dose). Only the efficacy data for the first function of G-CSF (reducing incidence of febrile neutropenia) was obtained from a systematic review. Efficacy data for the other two functions of G-CSF were estimated based on assumptions, and are in contrast with more direct evidence: Sung et al (2007), Papaldo et al (2005), Pettengell (2008), and Shitara, et al., 2011)

29: This study is looking at a combined effectiveness of chemotherapy and G(M)-CSF, not just G(M)-CSF. Doesn't look at all interventions of interest.

Table 5.11Incremental costs and effectiveness by treatment strategy for solid tumour patients who can take quinolone (baseline risk of neutropenic sepsis of one course of chemotherapy: 34.41%)

Strategy	Total costs (£)	Total QALYs	Incremental costs (£)	Incremental QALYs	ICER (£) versus baseline (QALYs)	ICER (£) incremental (QALYs)
Primary prophylaxis with quinolone	£270.4	-8.9*10^-4	—	—	Comparator	Comparator
Secondary prophylaxis with quinolone	£423.7	-1.9*10^-3	£153.3	-1.0*10^-3	Dominated	Dominated
Nothing/Placebo	£473.9	-2.3*10^-3	£203.5	-1.4*10^-3	Dominated	Dominated
Secondary prophylaxis with PEG-G-CSF	£773.6	-1.8*10^-3	£503.2	-8.9*10^-4	Dominated	Dominated
Primary prophylaxis with PEG-G-CSF	£2170.2	-5.6*10^-4	£1,899.8	3.3*10^-4	£5.7 million	£5.7 million

Table 5.12Incremental costs and effectiveness by treatment strategy for solid tumour patients who can not take quinolone (baseline risk of neutropenic sepsis of one course of chemotherapy: 34.41%)

Strategy	Total costs (£)	Total QALYs	Incremental costs (£)	Incremental QALYs	ICER (£) versus baseline (QALYs)	ICER (£) incremental (QALYs)
Nothing/Placebo	£473.9	-2.3*10^-3	—	—	Comparator	Comparator
Secondary prophylaxis with PEG-G-CSF	£773.6	-1.8*10^-3	£299.7	4.7*10^-4	£0.6 million	£0.6 million
Secondary prophylaxis with G(M)-CSF	£898.3	-2.0*10^-3	£424.3	2.4*10^-4	£1.8 million	Dominated
Primary prophylaxis with PEG-G-CSF	£2170.2	-5.6*10^-4-	£1,696.3	1.7*10^-3	£1.0 million	£1.0 million
Primary prophylaxis with G(M)-CSF	£2826.9	-1.3*10^-3	£2352.9	9.2*10^-4	£2.6 million	Dominated

Table 5.13Incremental costs and effectiveness by treatment strategy for non-Hodgkin lymphoma patients (baseline risk of neutropenic sepsis of one course of chemotherapy: 44.22%)

Strategy	Total costs (£)	Total QALYs	Incremental costs (£)	Incremental QALYs	ICER (£) versus baseline (QALYs)	ICER (£) incremental (QALYs)
Nothing/Placebo	£729.2	-3.3*10^-3	—	—	Comparator	Comparator
Secondary prophylaxis with PEG-G-CSF	£1,510.7	-2.9*10^-3	£781.4	6.7*10^-4	£1.2 million	£1.2 million
Secondary prophylaxis with G(M)-CSF	£1,629.0	-2.6*10^-3	£899.7	3.2*10^-4	£2.8 million	Dominated
Primary prophylaxis with PEG-G-CSF	£4,238.1	-2.1*10^-3	£3,508.9	2.2*10^-3	£1.6 million	£1.8 million
Primary prophylaxis with G(M)-CSF	£5,242.0	-1.1*10^-3	£4,512.8	1.1*10^-3	£4.1 million	Dominated

Table 5.14Incremental costs and effectiveness by treatment strategy for Hodgkin lymphoma patients (baseline risk of neutropenic sepsis of one course of chemotherapy: 20.27%)

Strategy	Total costs (£)	Total QALYs	Incremental costs (£)	Incremental QALYs	ICER (£) versus baseline (QALYs)	ICER (£) incremental (QALYs)
Nothing/Placebo	£235.8	-1.2*10^-3	—	—	Comparator	Comparator
Secondary prophylaxis with G(M)-CSF	£1,608.8	-1.1*10^-3	£1,372.0	7.5*10^-5	£18.2 million	£18.2 million
Primary prophylaxis with G(M)-CSF	£11,921.8	-9.3*10^-4	£11,686.0	2.5*10^-4	£47.2 million	£59.9 million

Recommendations

For adult patients (aged 18 years and older) with acute leukaemias, stem cell transplants or solid tumours in whom significant neutropenia (neutrophil count 0.5 × 10⁹ per litre or lower) is an anticipated consequence of chemotherapy, offer prophylaxis with a fluoroquinolone during the expected period of neutropenia only
Rates of antibiotic resistance and infection patterns should be monitored in treatment facilities where patients are having fluoroquinolones for the prophylaxis of neutropenic sepsis¹⁶.
Do not routinely offer granulocyte-colony stimulating factor (G-CSF) for the prevention of neutropenic sepsis in adults receiving chemotherapy unless they are receiving G-CSF as an integral part of the chemotherapy regimen or in order to maintain dose intensity.

16: For more information see the Department of Health's Updated guidance on the diagnosis and reporting of Clostridium difficile and guidance from the Health Protection Agency and the Department of Health on Clostridium difficile infection: how to deal with the problem.

Research recommendation

Randomised studies should investigate primary prophylaxis of neutropenic sepsis in 2 populations: children and young people (aged under 18) having treatment for solid tumours or haematological malignancies, or stem cell transplantation; and adults (aged 18 and older) diagnosed with lymphoma. The studies should compare the effectiveness of fluoroquinolone antibiotics given alone, fluoroquinolone antibiotics given together with granulocyte-colony stimulating factor (G-CSF) preparations, and G-CSF preparations given alone. Outcome measures should include overall mortality, infectious episodes and adverse events. In addition, quality of life should be determined using quantitative and qualitative methods. The resulting data should be used to develop a cost-effectiveness analysis comparing these 3 forms of prophylaxis in children and young people having anticancer treatment, and in adults diagnosed with lymphoma.