Clinical Practice Guideline Update on the Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy

Anthony J. Perissinotti, PharmD BCOP
Clinical Pharmacist Specialist, Inpatient Hematology
Clinical Team Leader—Hematology/Oncology
Adjunct Clinical Assistant Professor
University of Michigan Health System
Ann Arbor, MI

The American Society of Clinical Oncology (ASCO), in partnership with the Infectious Diseases Society of America (IDSA), released a new clinical practice guideline, “Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy,” on February 20, 2018.¹ This was an update to ASCO’s 2013 “Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia” guideline, but it shifts the focus toward outpatient treatment of febrile neutropenia (FN) rather than prophylaxis.² To decrease confusion, prophylaxis was not discussed in this update and will be treated separately in a future guideline.

Mortality associated with FN has dramatically declined since the advent of empiric broad-spectrum antimicrobials.^3-5 Discussions of antimicrobial stewardship should now begin, and healthcare resources for FN can be carefully decreased in selected patients. To this end, the update provides strong guidance on determining which patients can safely avoid hospitalization through the use of prognostic tools; it outlines specific diagnostic assessments and recommends treatment approaches to maintain patients in the outpatient setting.

ASCO and IDSA’s guideline development process consisted of a systematic literature review, critical appraisal, and final guideline approval. The review included six new updated meta-analyses and six new primary studies that were published after the release of the 2013 ASCO guideline. Major changes in the update are discussed below.

Traditionally the Multinational Association for Supportive Care in Cancer (MASCC) risk index or Talcott’s Rules have been used to determine patients’ FN risk (high versus low) and thus to identify candidates for outpatient therapy.^6,7 ASCO introduces a more recently validated tool, the Clinical Index of Stable Febrile Neutropenia (CISNE), which can predict major complications in patients with solid tumors. Results from the FINITE study demonstrated an increased accuracy in classifying the risk of FN complications with CISNE compared with the MASCC index or Talcott’s Rules.⁸ CISNE was specifically designed for patients with solid tumors who are clinically stable and who recently received mild- or moderate-intensity chemotherapy. According to ASCO, patients are initially scored via the MASCC index or Talcott’s Rules. Those with a MASCC score lower than 21 and those meeting criteria for Talcott’s groups 1–3 are deemed high risk and should receive inpatient therapy. Patients with a MASCC score of 21 or higher or in Talcott’s group 4 are then assessed via CISNE. Patients with CISNE scores of 3 or higher should receive inpatient management; patients with a CISNE score of 1 or 2 can be considered for outpatient management. Of note, patients who have acute leukemia or who are undergoing hematopoietic cell transplantation are unlikely to meet the criteria for outpatient management. In addition, patients who are already receiving a fluoroquinolone for FN prophylaxis are not candidates for outpatient therapy. See tables 1–4 in the full guideline for a comprehensive list of risk stratification and scoring systems that can be used to identify patients appropriate for outpatient management of FN.

Initial empiric therapy has not changed in the updated guideline and continues to follow standard guidelines from ASCO, IDSA, and the National Comprehensive Cancer Network (NCCN), which consist of monotherapy with an antipseudomonal beta-lactam unless the patient is unstable or has an allergy or when the presence of a multidrug-resistant (MDR) organism is suspected.^2,9,10 Patients who have been fully assessed and are deemed to be at low risk and those ready for outpatient management should receive oral empiric therapy with an antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin are now both considered first-line options) combined with amoxicillin/clavulanate. For patients with a penicillin allergy, clindamycin can be substituted for amoxicillin/clavulanate. Despite this recommendation, it is not common practice to employ both levofloxacin and amoxicillin/clavulanate. Many clinicians prescribe either ciprofloxacin with amoxicillin/clavulanate (because of poor streptococcal coverage with ciprofloxacin), levofloxacin monotherapy, or, in selected patients, a nonantipseudomonal-based therapy such as moxifloxacin, cefpodoxime, or amoxicillin/clavulanate.

Additional changes to the previous guideline include more direction on how to manage fluoroquinolone resistance, extended-spectrum beta-lactamase (ESBL)–producing gram-negative bacilli, carbapenem-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, and other MDR organisms. These patients should be considered for initial empiric therapy with intravenous antibacterials targeting their regional resistance patterns (for ESBL- producing bacilli: carbapenem; for carbapenem-resistant organisms: polymyxin-colistin, tigecycline, ceftazidime/avibactam, or ceftolozane/tazobactam; for MRSA: vancomycin, linezolid, or, if there is no evidence of pneumonia, daptomycin; and for VRE: daptomycin or linezolid).

The updated guideline strengthens confidence in clinicians’ ability to manage FN in the outpatient setting. The introduction of CISNE has improved the ability to identify patients who can safely avoid hospital admission, reduce their length of stay in overcrowded emergency departments, reduce their exposure to MDR hospital-acquired pathogens, and improve their satisfaction by being treated in the comfort of their own home. This model of care is of utmost importance now and in the future, especially given the increased attention to the Oncology Care Model (OCM). OCM provides financial incentives for participating centers and encourages value-based care or high-quality cost-effective care. The ASCO/IDSA guideline is an excellent resource to aid in maintaining safe, high-quality management of oncology patients while improving patient satisfaction and reducing the significant costs associated with hospital admission. 

References

1. Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018;36(14):1443-1453.
2. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31(6):794-810.
3. Schimpff S, Satterlee W, Young VM, et al. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med. 1971;284(19):1061-1065.
4. Klastersky J, Cappel R, Debusscher L. Evaluation of gentamicin with carbenicillin in infections due to gram-negative bacilli. Curr Ther Res Clin Exp. 1971;13(3):174-181.
5. Viscoli C, Varnier O, Machetti M. Infections in patients with febrile neutropenia: epidemiology, microbiology, and risk stratification. Clin Infect Dis. 2005;40S4:S240-S245.
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 neutropenic cancer patients. J Clin Oncol. 2000;18(16):3038-3051.
7. Talcott JA, Siegel RD, Finberg R, et al. Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. J Clin Oncol. 1992;10(2):316-322.
8. Carmona-Bayonas A, Jiménez-Fonseca P, Virizuela Echaburu J, et al. Prediction of serious complications in patients with seemingly stable febrile neutropenia: validation of the Clinical Index of Stable Febrile Neutropenia in a prospective cohort of patients from the FINITE study. J Clin Oncol. 2015;33(5):465-471.
9. 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.
10. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections. V.1.2018. National Comprehensive Cancer Network, Inc. 2017. Accessed May 14, 2018