Validation of a Risk Model for Hospitalized Adult Cancer Patients with Febrile Neutropenia.
Authors: Kuderer Nicole M. , Crawford Jeffrey , Dale David C. , Lyman Gary H. ,   for the ANC Study Group
Published: October 2019

Abstract
Introduction: Febrile neutropenia (FN) represents the most common dose-limiting toxicity associated with systemic chemotherapy and is associated with considerable morbidity and mortality. The majority of patients with FN are hospitalized for evaluation and administration of empiric broad-spectrum antibiotics. A risk model for mortality in hospitalized adult cancer patients with FN has previously been reported (Kuderer, ASCO 2004). Validation of this risk model in an independent population of hospitalized patients with FN is presented.
Methods: Risk model development was based on the records of 40,163 adult non-transplant cancer patients hospitalized with FN at one of 115 academic medical centers reporting to the University HealthSystem Consortium between 1995 and 2000. A risk score for mortality was estimated for each patient based on a weighted summary of all significant variables in a logistic regression model including age, cancer diagnosis, comorbidities (heart, liver, renal, cerebrovascular, pulmonary embolism) and complications (gram+ and gram- sepsis, fungal infection, pneumonia, hypotension, hypovolemia, ICU admission). The risk score was classified into low risk (0–4); intermediate (5–9); high (10–14); and very high (15–22).
Results: To validate the FN mortality risk score, it is applied here to an independent population of 16,379 adult cancer patients hospitalized with FN at academic medical centers between 2001–2002. Inpatient mortality was reported in 1,452 (8.9%). Although patients ≥65 years of age represented 30% of the inpatient FN population, they accounted for 43% of deaths. Application of the previously developed risk model to this independent population provided adjusted estimates of relative risk (odds ratios) of: age ≥ 65 (1.5); leukemia (1.3); lung cancer (1.3); heart (1.4); liver (2.1); renal (3.0); cerebrovascular (3.6); pulmonary embolism (2.8); gram+ sepsis (2.1); gram- sepsis (2.4); fungal (1.4); pneumonia(1.8); hypotension (1.9); hypovolemia (1.6) and ICU (3.7) (Global χ2:P<.0001). All significant covariates in the development phase remained significant in the validation study. As shown in the table, the model demonstrated excellent fit (P<.0001) and a high level of discrimination for inpatient mortality (R2 = 0.81; c-statistic = 0.85 [0.84, 0.86]; P<.0001).
Risk Score Category Low (0–4) Int (5–9) High (10–14) Very High (15+) Development Phase Patients (%) 74.6 20.6 4.3 0.4 Deaths (%) 3.1 18.9 48.1 64.6 Validation Phase Patients (%) 68.5 23.3 7.0 1.2 Deaths (%) 2.5 14.4 42.3 68.8
Test performance among the 22% of patients with a predicted risk of mortality of ≥10% include: sensitivity: 71%; specificity: 83%; positive predictive value: 29%; negative predictive value: 97%; likelihood ratio positive: 4.2; likelihood ratio negative: 0.3; diagnostic odds ratio: 12.2 [10.8, 13.8]. A low risk subgroup (23%) was also identified with a risk <1%. Similar validation was achieved of previously reported models for length of stay and cost.
Conclusions: Previously reported risk models for mortality, length of stay and cost have been validated in a separate population of adult cancer patients hospitalized with FN. These validated models may assist clinicians in identifying both high-risk patients for more aggressive supportive care measures as well as low risk patients as candidates for early discharge. The cost-effectiveness of these models in assisting clinical decision-making is currently under study.