is defined as: - Fever higher than 38.3C OR higher than 38.0C for more than 1 hour, in a patient who has received chemotherapy in the past month, AND - Neutrophils less than 0.5 x 10 9 cells/L 2. Patients suspected of having febrile neutropenia should undergo: - History and physical exam to determine the site of infection - Complete hematological profile and chemistry profile, including blood cultures, urine cultures, and nasopharyngeal swab if respiratory symptoms are present - Chest-x-ray 3. The preferred initial antibiotic therapy is intravenous piperacillin-tazobactam 4.5 grams IV every 8 hours, plus intravenous fluids. Cefepime monotherapy is an alternative to piperacillin-tazobactam for penicillin-allergic and anaphylactic patients. 4. Patients with febrile neutropenia who are felt to be at low risk of complications may be managed as outpatients. 5. Neutropenia alone is expected for patients receiving chemotherapy; therefore asymptomatic neutropenia without fever is not an oncologic emergency.# Important Contact Information
After assessing the patient, call the responsible medical oncologist or the after-hours medical oncologist on-call for a consultation:
- If septic shock is a concern, physicians and health-care providers can call the RAAPID line once the patient has been stabilized:
- Northern Alberta: 1-800-282-9911
- Southern Alberta: 1-800-661-1700
Febrile neutropenia is considered an oncologic and medical emergency. Mortality rates of 5 to 20% have been reported. 1,2 More than 70% of patients presenting with febrile neutropenia have an underlying hematological disease (e.g., leukemia, lymphoma, other), while the majority of remaining cases often present with underlying neoplasms (i.e., solid tumours) or multiple myeloma. 3 Chemotherapy has been reported as the cause of neutropenia in nearly 90% of cases. 3 Solid tumours requiring chemotherapy that CLINICAL PRACTICE GUIDELINE SUPP-004 Version 3
may put patients at an increased risk of febrile neutropenia include breast cancer, colorectal cancer, lung cancer (small cell and non-small cell), and ovarian cancer.  The use of empiric broad-spectrum antibiotics has significantly reduced the mortality and morbidity of this common chemotherapy complication. However, rapid assessment and institution of the appropriate antibiotics are of paramount importance. A patient on chemotherapy should not wait in the emergency department for assessment for an extended period of time; ideally a system would be in place for the rapid identification of a potential patient with febrile neutropenia who would then immediately have a complete blood count (CBC) drawn and urgent assessment by a health care professional.
The objective of this guideline is to provide clinicians (i.e., emergency room physicians and nurses) and family physicians with strategies for the management of adult patients with solid tumours or hematologic malignancies who present with febrile neutropenia.

# GUIDELINE QUESTIONS
- What is the definition of febrile neutropenia for adult patients with solid tumours or hematologic malignancies?
- What are the risk factors for febrile neutropenia?
- What pre-treatment investigations should be conducted for adult outpatients suspected of having febrile neutropenia?
- What antibiotic therapy regimens are recommended for the treatment of febrile neutropenia in adult patients with solid tumours or hematologic malignancies?
- What are the recommended management strategies for adult patients with low-risk febrile neutropenia?

# DEVELOPMENT AND REVISION HISTORY
The original version of this guideline was created and reviewed by the Alberta Medical Affairs and Community Oncology (MACO) Medical Liaison Team in November 2008; the guideline was updated and approved by the MACO team in January 2012 and was reviewed and approved by members of the CancerControl Alberta Medical Liaison Committee in January 2014. For the development of the original guideline, evidence was selected, reviewed, and endorsed by a working group comprised of oncologists specializing in breast, ovarian, colorectal, and lung cancers, hematologists, and family physicians, as well as two Knowledge Management Specialists from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
In order to achieve consensus on the key points in the original guideline, a survey based on the AGREE II instrument was sent to oncologists, hematologists, infectious diseases specialists, and family physicians. 7,8 The survey contained items that asked reviewers to rate their level agreement with each of the key points, as well as their level of agreement that the key points were evidence-based. Other survey items included level of agreement that the guideline questions, search strategy, and target audience were each clearly described, overall agreement with the guideline, and willingness to recommend use of the guideline. For all items, a 7-point scale, ranging from strongly agree (7) to strongly disagree (1), was CLINICAL PRACTICE GUIDELINE SUPP-004 Version 3 used. Respondents were also permitted to provide open-ended comments on each item. A total of eight reviewers responded with feedback. There were five medical oncologists, one family physician, one infectious diseases specialist, and one general internist working mainly in oncology, representing Calgary, Edmonton, Red Deer, Grande Prairie, and Medicine Hat. Survey items that achieved a score of 6 to 7 from at least 80% of the reviewers were deemed acceptable without further edits; all other survey items were deemed important areas for consideration and/or revision. Overall, revisions were considered for the following eight items: target population, key points #2, #3, and #4, contact information, balance of benefits and risks, linkage of the recommendations to the evidence base, and appearance of the key recommendations. The guideline was then edited to better reflect the majority opinion.

# SEARCH STRATEGY
For Articles were excluded from the final review if they: had a non-English abstract, involved only pediatric patients, or were published prior to January 1985. A systematic search for new or updated practice guidelines published since January 2010 was also conducted. Guidelines from the National Comprehensive Cancer Network (NCCN), British Columbia Cancer Agency (BCCA), and Infectious Diseases Society of America (IDSA) were deemed to be most relevant and corresponded best with local context and practice.

# TARGET POPULATION
The following recommendations apply to adult outpatients who have been treated with chemotherapy for solid tumours or hematologic malignancies within the past month and who present with febrile neutropenia. Different principles may apply to inpatients and to pediatric patients.

# RECOMMENDATIONS AND DISCUSSION
The following are guidelines for the management of adult cancer patients with febrile neutropenia. Every patient has a unique presentation and should be managed as such. Daily reassessments are required to ensure that the patient is recovering satisfactorily.

# Who to Contact
The on-call medical oncologist or responsible medical oncologist (if available) should be contacted when any patient with cancer presents with febrile neutropenia. The responsible medical oncologist should be contacted for any additional or ongoing concerns relating to the care of a cancer patient with febrile CLINICAL PRACTICE GUIDELINE SUPP-004 Version 3 neutropenia. Another useful resource is the on-call infectious diseases specialist at the University of Alberta Hospital (Edmonton) or at the Foothills Hospital (Calgary).

# Guideline Question 1. How is febrile neutropenia defined?
The working group reviewed several descriptions of febrile neutropenia from published studies; 9-20 in addition, definitions included in published clinical practice guidelines were reviewed and are summarized below in Table 1.   Based on a review of the descriptions in Table 1, the working group agreed on the following consensus definitions:
- Fever: Fever is usually defined by a single oral temperature higher than 38.3C or a sustained oral temperature higher than 38.0C for more than one hour.
- Neutropenia: Neutropenia is defined by an absolute neutrophil count (ANC) less than 0.5x10 9 cells/L or an ANC less than 1.0x10 9 cells/L with an expected fall to less than 0.5x10 9 cells/L within the next 48 hours.

# Guideline Question 2. What are the risk factors for febrile neutropenia?
Advanced age is one of the most common risk factors for developing febrile neutropenia; 28

# Guideline Question 3. What pre-treatment assessments and investigations should be performed?
A careful history and detailed examination is required for all cancer patients suspected of having febrile neutropenia. The examination should include assessments of: 21,22 - Mental status A chest x-ray should be obtained even in the absence of pulmonary symptoms or signs. Pulmonary infiltrates may not develop until the neutropenia begins to recover. Thoracic CT has not been shown to improve outcomes in the absence of clinical pulmonary abnormalities but can be considered in the setting of clinical abnormalities and a normal chest x-ray. Other imaging tests should be guided by the clinical picture.