Outpatient Treatment for Low-Risk Febrile Neutropenia

Rivas-Ruiz R, Villasis-Keever M, Miranda-Novales G, Castelán-Martínez OD, Rivas- Contreras. Outpatient treatment for people with cancer who develop a low-risk febrile neutropaenic event. Cochrane Database Syst Rev. 2019 Mar 19;3:CD009031.

Study Population: 10 trials including 994 low risk patients (628 adults, 366 children) with cancer, fever, and neutropenia.

Treatment failure, mortality

Adverse drug reactions

Fever and infection are common in neutropenic cancer patients.1^,2 While some become severely ill, most patients have an uneventful course, with 50-60% having no life-threatening complication or fatal infection.1^,2 Patients with febrile neutropenia have therefore been divided into low-risk and high-risk groups. Those patients at low-risk of complications may benefit from outpatient management.1^,2 Admission to the hospital has its own risks, including iatrogenic infections and reduced quality of life.1 Guidelines thus recommend risk stratification for potential outpatient treatment.3^,4 However, it is important to determine if outpatient management is as safe and effective as inpatient management in low-risk patients.

This systematic review and meta-analysis5 included randomized controlled trials that compared inpatient antimicrobial therapy with outpatient antimicrobial therapy for low-risk febrile neutropenic adults or children with cancer. The primary outcomes were treatment failure (death, non-resolution of signs or symptoms of presenting infection, or change of antibiotic) and mortality at 30 days.

The authors identified 10 relevant studies (n=994), six in adults (n=628) and four in children (n=366). Definitions for low risk were not standardized, but generally required that patients not a) need hospitalization, b) have focal or severe infection, c) have relapse of the disease, and d) be receiving intensive chemotherapy. Overall, there were no difference in treatment failure (relative risk [RR] 0.81, 95% confidence interval [CI] 0.32 to 2.71) or mortality (RR 1.11, 95% CI 0.41 to 3.05). Among adults there was no difference in treatment failure (RR 1.2, 95% CI 0.8 to 1.9) or mortality (RR 1.0, 95% CI 0.3 to 3.7). Among pediatric patients, there was also no difference in treatment failure (RR 1.0, 95% CI 0.6 to 2.0) or mortality (RR 0.6, 95% CI 0.2 to 2.7). Hospitalization duration, a secondary outcome, was 1.64 days lower in the adult outpatient group (95% CI -2.22 to 1.06) and 3.9 days lower in the pediatric outpatient group (95% CI 95% CI -5.37 to - 2.43). The risk of adverse drug reactions (harm endpoint) was not statistically significant between the two groups (low quality evidence).

While this review suggests no significant difference in treatment failure or mortality between inpatient and outpatient management, patients were observed for 24 to 72 hours in the hospital before discharge in 6 trials and discharged immediately in only 2 trials. Despite this, there was still a reduction in patient hospitalization and length of stay. The certainty of this estimate was considered low, however, based on potential bias and quality of evidence.

Additionally, low-risk criteria varied between studies with only one utilizing Multinational Association for Supportive Care in Cancer (MASCC) criteria and none using Clinical Index of Stable Febrile Neutropenia (CISNE) criteria, the two currently recommended tools.3^,4^,5 There are no existing criteria for low-risk stratification in pediatric patients with neutropenic fever. Moreover, there were differences in types and routes of antibiotic regimens and types of cancers (eg, bloodborne versus solid tumors). There was also limited reporting on randomization and allocation concealment. Evidence quality of the included RCTs was low to moderate based on the GRADE approach, and confidence intervals were wide for main outcome measures. Finally, the studies may have been underpowered for their primary outcomes due to low sample sizes in several trials.

Despite the above limitations, these findings suggest outpatient treatment of selected low-risk patients with cancer and febrile neutropenia was, in these investigations, as safe as inpatient management. We have assigned a color recommendation of Yellow (Unclear if Benefits) both because the only quantifiable benefit was a secondary measure, and because of the low certainty of this finding. Clearly, larger, high quality trials are needed to establish with more certainty the promising benefits suggested by these data.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

September 3, 2019