Patients with MASCC scores 21 or in Talcott group 4, and without other risk factors, can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of empiric antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin, if penicillin allergic) is recommended as empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed.

The first guideline1 published by the American Society of Clinical Oncology (ASCO) provided recommendations on uses of hematopoietic colonystimulating factors (CSFs), including primary prophylaxis of fever and neutropenia (FN) in patients undergoing chemotherapy for malignancy if their risk was 40%. ASCO has updated this guideline periodically, most recently in 2006,2 when the threshold for primary prophylaxis with a CSF was revised to include patients at 20% risk for FN. Although the CSF guideline is scheduled for another update soon, ASCO has not previously addressed other measures (eg, prophylactic antimicrobial drugs or protective environments) to prevent infection in outpatients who are neutropenic, not yet febrile, and either continue to receive or have recently completed chemotherapy for malignancy.

 Additionally, a priority-setting exercise of the ASCO Clinical Practice Guidelines Committee (CPGC) selected outpatient management of febrile neutropenia as an important topic for a new guideline Managing FN in oncology patients began to change in the late 1960s and early 1970s, when evidence emerged that empiric antibacterial therapy reduced deaths resulting from infection, compared with waiting for results of microbiologic assays.3-7 The spectrum of bacterial pathogens most commonly isolated from patients with FN during or after treatment for malignancy shifted from mostly Gram-negative species in the 1960s and 1970s to more Gram-positive species in the 1980s and 1990s. Currently, coagulase-negative staphylococci are the most common species identified in blood cultures, but the frequency of antibiotic-resistant Gram-negative bacterialinfectionsisincreasing. However, blood cultures and other cultures are negative and the causative organism and site of infection uncertain in many oncology patientswithfever. Becauseinfection can progress rapidly and become life threatening if patients are neutropenic, clinical practice guidelines recommend administration of broad-spectrum antibacterials (using monotherapy or a combination regimen) soon (within an hour) after fever is documented in a neutropenic patient.7-13 Until the late 1980s and early 1990s, empiric antibacterial therapy wasalmostinvariablyadministeredintravenously (IV)in thehospitalifan oncology patient developed FN. Presently, a wider spectrum of disorders than ever before is being managed on an outpatient basis. 

Potential advantages of outpatient management include increased convenience for patientsand theirfamilymembers, reduced costs of care,and, particularly for those at risk of infection, decreased exposure to hospital-acquired infections, which often may be resistant to the antibiotics used most frequently. Malignancies currently being treated outside the hospital range from adjuvant systemic therapy for breast cancer to postremission consolidation with high-dose cytarabine for acute myeloid leukemia to reduced-intensity conditioning stem-cell transplantation (SCT). Various approaches have been studied to stratify such patientswho develop FN by risk for medical complications or death.14-21 Several of these approaches have been used to selectlow-risk patientsfor early discharge or outpatient therapy, and a number of trials randomly assigninglow-risk patients have comparedoutcomesofinpatientversusoutpatientmanagement14,21-25or oral versus IV antibacterials as empiric therapy.14,26,27 In light of the evidencefrom such studies, theASCOCPGCassembledapanelofexperts to address the following clinical questions. A. What interventions are appropriate to prevent infections in patients with a malignancy who have received chemotherapy in an inpatient or outpatient setting and who are, or are anticipated to become, neutropenic as outpatients?

 A-1. How should risk of developing a febrile neutropenic episode (FNE) be assessed in such patients who are not yet febrile? What clinical characteristics identify patients who should be offered antimicrobial prophylaxis? A-2. What antimicrobial drug classes should be used to prevent infection in afebrile neutropenic outpatients who should be offered prophylaxis? A-3. What additional precautions are appropriate to prevent exposure of neutropenic but afebrile outpatients with a malignancy to infectious agents or organisms? B. Which patients with a malignancy and febrile neutropenia are appropriate candidates for outpatient management? B-4. What clinical characteristics should be used to select patients for outpatient empiric therapy? B-5. Should outpatients with FN at low risk for medical complications receive their initial dose(s) of empiric antimicrobial(s) in the hospital or clinic and be observed, or can some selected for outpatient management be discharged immediately after evaluation? B-6. What psychosocial and logistic requirements must be met to permit outpatient management of patients with FN? C. What interventions are indicated for patients with a malignancy and febrile neutropenia who can be managed as outpatients? C-7. What diagnostic procedures are recommended? C-8. What antibacterials are recommended for outpatient empiric therapy? C-9. What additional measures are recommended for outpatient management? C-10. How should persistent neutropenic fever (PNF) syndrome be managed?

Literature Review and Analysis Literature search strategy. The MEDLINE database was searched using PubMed for relevant evidence published from 1987 through the end of April 2011. The search included terms for malignant diseases linked to terms for neutropenia, fever, or infection and to terms for clinical trials, systematic reviews, meta-analyses, or clinical guidelines. Data Supplement 1 provides the full search strategy (online at www.asco.org/guidelines/outpatientfn). One reviewer selected articles for full-copy retrieval and consulted a Panel cochair when potential relevance was uncertain. Reference lists of articles retrieved in full copy were searched for other relevant reports. Panel members provided additional references from personal files. Inclusion and exclusion criteria. Articles were selected for inclusion in the systematic review if they were fully published English-language reports on: antimicrobials for prophylaxis of infection in oncology outpatients with neutropenia from chemotherapy, development and/or validation of methods to stratify risk of complications in oncology patients with FN, empiric antimicrobial therapy for oncology outpatients with FN, or direct comparisons of outcomes for inpatient versus outpatient management of oncology patients with FN. For clinical questionsaddressingantimicrobialsforprophylaxis ofinfection or as empiric therapyfor FN, study selection criterialimitedinclusion to reportsfrom randomized controlled trials (RCTs) of adult human participants, systematic reviews and meta-analyses of RCTs, or evidence-based clinical practice guidelines.

 Prospective or retrospective cohort studies, case-control studies, and case series were included for questions addressing risk stratification or direct comparison of inpatient versus outpatient management. Meeting abstracts, letters, commentaries, editorials, case reports, and nonsystematic (narrative) reviews were excluded from evidence tables for all questions. Data extraction. For studies on afebrile neutropenic outpatients, primary outcomes included: 1) febrile episodes and 2) infections, whereas secondary outcomes included infection-related mortality. For studies on outpatients with FN, primary outcomes included: 1) empiric treatment success (defined as recovery from FN without medical complications) and 2) overall and infection-related mortality, whereas secondary outcomes included: 1) defervescence without regimen change, 2) time to defervescence, 3) complications from infection, and 4) relapsed or recurrent fever. Additional secondary outcomes relevant to both sets of studies included: 1) hospital admissions, 2) duration of hospital stay, and 3) adverse effects of antimicrobials. Data were extracted directly into evidence tables (see Data Supplement Tables DS-3 to DS-9; online at www.asco.org/guidelines/outpatientfn) by one reviewer and checked for accuracy by a second reviewer. Disagreements were resolved by discussion and by consultation with Panel cochairs if necessary. Guideline Development Process The entire Panel met once to review results of the systematic review; additional work to revise the clinical questions and to draft guideline recommendations and amanuscriptwas completed by telephone conferences (when necessary) and electronic review of documents.

 All members of the Panel participated in preparation and revision of the draft guideline document and approved the final version submitted for peer review and publication in Journal of Clinical Oncology. Additional feedback was solicited from external reviewers. The content of the guidelines and manuscript were reviewed and approved by the ASCO CPGC before publication. Definition of Terms For purposes of this guideline, the Panel defined neutropenia as an absolute neutrophil count (ANC)
1,000/
L (equivalent to
1.0 109 /L), severe neutropenia as ANC
500/
L (equivalent to
0.5 109 /L), and profound neutropenia as ANC
100/
L (equivalent to
0.1 109 /L). The Panel defined the state of being febrile as a temperature of 38.3°C by oral or tympanic thermometry, but it did not exclude evidence from studies that used slightly different definitions (eg, core temperature 38°C). Guideline Policy The practice guideline is not intended to substitute for the independent professional judgment of the treating physician. Practice guidelines do not account for individual variation among patients and may not reflect the most recent evidence. This guideline does not recommend any particular product or course of medical treatment. Use of the practice guideline is voluntary. Guideline and Conflicts of Interest The Expert Panel was assembled in accordance with the ASCO Conflict of Interest Management Procedures for Clinical Practice Guidelines 

. Members of the Panel completed the ASCO disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as the result of promulgation of the guideline. Categories for disclosure include employment relationships, consulting arrangements, stock ownership, honoraria, research funding, and expert testimony. In accordance with the Procedures, the majority of the members of the Panel did not disclose any such relationships. Revision Dates At annual intervals, the Panel cochairs and two Panel members designated by the cochairs will determine the need for revisions to the guideline based on an examination of current literature. If necessary, the entire Panel or an update committee will be reconvened to discuss potential changes. When appropriate, the Panel will recommend revised guidelines to the ASCO CPGC for review and approval. RESULTS The MEDLINE search identified a total of 4,863 unique records. Review of titles and abstracts eliminated 4,397 as either not relevant to the clinical questions of the guideline or not meeting study selection criteria (Data Supplement 2; online at www.asco.org/guidelines/ outpatientfn). Of 466 articles selected for full-text retrieval, 45 met study selection criteria for data extraction. Hand-searching of reference lists from included articles and input from Panel members identified 140 additional articles retrieved in full, of which two met selection criteria. 

Of the 47 articles extracted, none addressed guideline Key Question A (preventing infection in neutropenic adult outpatients who are not febrile); 25 addressed Key Question B (selecting adult patients with FN who are eligible for outpatient management; Data Supplement Tables DS-3 to DS-6), and 22 addressed Key Question C (comparing interventions used to manage FN in the outpatient setting). Data extracted from the 47 reports that met selection criteria are listed in Data Supplement Tables DS-3 to DS-9. Other Guidelines and Consensus Statements Other organizations have published guidelines or consensus statements addressing clinical questions also addressed here. These include guidelines on managing FN in patients with cancer from the Japan Febrile Neutropenia Study Group,9 the European Society of Medical Oncology (ESMO),10 and an Australian consensus panel.13,21,28,29 Additionally, the National Comprehensive Cancer Network (NCCN) has published guidelines on prevention and treatment of cancer-related infections,11 and the Infectious Disease Society of America (IDSA)7,12 and the Infectious Diseases Working Party of the German Society of Hematology and Oncology8 have published guidelines on uses of antimicrobial drugs in neutropenic patients with cancer. The Panel has evaluated the recommendations of these organizations and found them to be generally consistent with recommendations in this ASCO clinical practice guideline. Specific differences are highlighted and discussed in the Literature Review and Analysis sections that follow each recommendation.