Febrile neutropenia (FN) is a relatively common adverse event associated with myelosuppressive cancer therapies. FN typically leads to immediate hospitalization, and can have significant negative effects on patient outcome.

In neutropenic patients, fever may be the only indication of infection, as neutrophil loss impedes other responses to infection.1 In patients with FN, 50% to 60% actually develop an infection.1-3

A study in the United States found a 9.5% overall associated mortality rate for patients with FN that varied by the presence and type of infection as well as the underlying cancer type. The median length of stay (LOS) for patients hospitalized for FN was approximately 6 days in this study, with costs increasing as LOS increased.4 Development of and hospitalization for FN often leads to chemotherapy-dose reductions or therapy interruptions; thus suboptimal cancer therapy be detrimental for patients’ outcomes.4,5

Adjunct Therapies for Febrile Neutropenia        

Current recommendations for treatment of FN take into account each individual patient’s risk for developing FN-related complications, based on a widely used scoring system from the Multinational Association for Supportive Care in Cancer.1,6  For most patients, empiric therapy using broad-spectrum antibacterial agents is recommended by the National Comprehensive Cancer Network (NCCN)2 and the European Society for Medical Oncology.3

Related: ASCO Issues Guideline for Febrile Neutropenia in Adults

Empiric therapy of FN does not recommend the use of either vancomycin nor granulocyte colony-stimulating factors (G-CSFs). As there is little or no evidence to support a clinical benefit in empiric use, vancomycin should be reserved for specific clinical indications, including presence of pneumonia, skin or soft tissue infection, catheter-related infection, or hemodynamic instability.1,2

Similarly, while there are solid data that support a role for G-CSF in prophylaxis of FN for patients undergoing chemotherapy,7 the data supporting a clinical benefit for these agents as an adjunct to antibacterial therapy in established FN are not as strong. To date, analyses have shown no survival benefit associated with G-CSF for treatment of FN.8

Thus, neither the American Society for Clinical Oncology nor the Infectious Diseases Society of America recommend G-CSF agents for treatment of established FN or as adjuncts to antibacterial therapy.1,9  The NCCN recommends consideration of G-CSFs only for patients at high risk for serious infectious complications (eg, progressive infections and invasive fungal infections).2,8

Guideline Use of Antibacterials in Clinical Practice

A group of researchers from Columbia University in New York, led by Jason D. Wright, MD, conducted a study of patients treated for solid tumors who were hospitalized with a primary diagnosis of FN; the researchers also evaluated how FN treatment in clinical practice deviates from guidelines. Their results were published in JAMA Internal Medicine earlier this year.

The researchers used the “Perspectives” database to capture patterns of FN treatment during the years 2000 to 2010. Patients were stratified as high risk (presence of ≥1 of the following: pneumonia, hypotension, sepsis, intensive care unit [ICU] admission, mechanical ventilation), or low risk (all others) for FN complications.

There were three primary end points: 1) use of guideline-based antibacterials; 2) use of vancomycin; and 3) use of G-CSF.10 In the study, empiric use of ceftazidime, cefepime, imipenem, meropenem, piperacillin/tazobactam, any aminoglycoside, alone or in combination with ciprofloxacin or ticarcillin/clavulanate, closely aligned with the agents and use recommended by NCCN.2,10

Their results revealed several interesting patterns in the empiric treatment of FN. Guideline-based use of antibacterials was high; however, so was nonrecommended use of vancomycin and G-CSF (Table 1). Treatment of FN also evolved over the 10-year study period. Guideline-based antibacterial use increased slightly, while use of vancomycin jumped from about 17% to 55% between 2000 and 2010 (Figure 1).10

Table 1. Treatment of Cancer Patients Hospitalized for Febrile Neutropenia10

Intervention Total Patients (N=25,231) High-risk Patients
Low-risk Patients
Guideline-based 78.9% 82.7% 77.8%
First-line vancomycin 36.9% 50.8% 33.1%
Empiric G-CSF 62.9% 65.9% 62.1%

Interestingly, the use of G-CSF declined significantly during the years covered in the study. In 2000, roughly three-quarters of patients hospitalized for FN received G-CSF, whereas in 2010, the number had dropped to a little over half. Among patients who received G-CSF, more than a third received the drug for a time period (1 to 2 days) that was unlikely to provide clinical benefit.10

In their analysis, the researchers identified several factors associated with guideline-based treatment, such as patients treated in more recent years, patients treated in teaching or high-volume hospitals that were more likely to receive vancomycin; and those with pneumonia or sepsis treated in the ICU. Hospital-based clinicians and physicians who treat a large number of patients with FN were more likely than other patients to use guideline-based antibacterials. However, the former tended to overuse vancomycin as well.10

Among low-risk patients, the use of guideline-based antibacterials led to lower risk for in-hospital mortality (odds ratio [OR]=0.65; 95% CI: 0.42-0.95) and lower risk for being discharged to a place other than home, such as a skilled nursing facility (OR=0.77; 95% CI: 0.65-0.92). The use of vancomycin or G-CSF by these patients did not affect outcomes.

Among patients categorized as high risk, none of the interventions were associated with significant risk reduction, although use of guideline-based antibacterials resulted in the lowest risk of death (OR=0.80; 95% CI: 0.59-1.09).10 Empiric use of vancomycin or G-CSF was associated with higher costs but no measurable improvement in outcome.10

Summary

An important takeaway is that appropriate use of guideline-based antibacterials led to improved outcomes for patients at low risk for FN, yet empiric use of vancomycin and G-CSF had no beneficial effect when taking into account additional costs of care. All current national and international guidelines for management of established FN in patients being treated for cancer recommend against empiric use of vancomycin and G-CSF except in very specific clinical circumstances. Adherence to these guidelines could benefit patients with cancer in terms of decreased mortality and morbidity, while also avoiding unnecessary clinical and economic costs.


References

1. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):e56-e93.

2. National Comprehensive Cancer Network. NCCN Clinical Practice Guideline: Prevention and treatment of cancer-related infections. Version 1.2013. www.nccn.org. Accessed August 15, 2013.

3. De Naurois J, Novitzky-Basso I, Gill MJ, et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2010;21(Suppl 5):v252-v256.

4. Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106(10):2258-2266.

5. Pettengell R, Johnson HE, Lugtenburg PJ, et al. Impact of febrile neutropenia on R-CHOP chemotherapy delivery and hospitalizations among patients with diffuse large B-cell lymphoma. Support Care Cancer. 2012;20:647-652.

6. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer Risk Index: a multinational scoring system for identifying low-risk febrile neutropenia patients. J Clin Oncol. 2000;18(16):3038-3051.

7. Cooper KL, Madan J, Whyte S, et al. Granulyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: a systematic review and meta-analysis. BMC Cancer. 2011;11:404-414.

8. National Comprehensive Cancer Network. NCCN Clinical Practice Guideline: Myeloid growth factors. Version 2.2013. www.nccn.org. Accessed August 26, 2013.

9. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(9):3187-3205.

10. Wright JD, Neugut AI, Ananth CV, et al. Deviation from guideline-based therapy for febrile neutropenia in cancer patients and their impact on outcomes. JAMA Intern Med. 2013;173(7):559-568.