Published Ahead of Print on January 5, 2015 as 10.1200/JCO.2014.57.

2347
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.57.2347

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

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
Alberto Carmona-Bayonas, Paula Jiménez-Fonseca, Juan Virizuela Echaburu, Maite Antonio, Carme Font,
Mercè Biosca, Avinash Ramchandani, Jerónimo Martínez, Jorge Hernando Cubero, Javier Espinosa,
Eva Martínez de Castro, Ismael Ghanem, Carmen Beato, Ana Blasco, Marcelo Garrido, Yaiza Bonilla,
Rebeca Mondéjar, María Ángeles Arcusa Lanza, Isabel Aragón Manrique, Aránzazu Manzano, Elena Sevillano,
Eduardo Castañón, Mercé Cardona, Elena Gallardo Martín, Quionia Pérez Armillas,
Fernando Sánchez Lasheras, and Francisco Ayala de la Peña
Author affiliations appear at the end of
this article. A B S T R A C T

Published online ahead of print at Purpose

www.jco.org on January 5, 2015.
Written on behalf of the Supportive
Care Working Group of the Spanish
Society of Medical Oncology.
To validate a prognostic score predicting major complications in patients with solid tumors and
seemingly stable episodes of febrile neutropenia (FN). The definition of clinical stability implies the
absence of organ dysfunction, abnormalities in vital signs, and major infections.

Presented in part at the 50th Annual Patients and Methods

Meeting of the American Society of
Clinical Oncology, Chicago, IL, May
30-June 3, 2014; Multinational Associa-
tion of Supportive Care in Cancer/Inter-
national Society of Oral Oncology
Symposium, Miami, FL, June 26-28,
2014; European Society for Medical
Oncology Congress, Madrid, Spain,
September 26-30, 2014; and Spanish
Society of Medical Oncology Sympo-
sium, Madrid, Spain, October 22-24,
2014.
Terms in blue are defined in the glos-
sary, found at the end of this article
and online at www.jco.org.
Authors’ disclosures of potential
conflicts of interest are found in the
article online at www.jco.org. Author
contributions are found at the end of
this article.
Corresponding author: Alberto
Carmona-Bayonas, MD, PhD, Hospital
Universitario Morales Meseguer, Calle
Marqués de los Vélez s/n, Murcia,
Spain; e-mail: alberto.carmonabayonas@
gmail.com.
We developed the Clinical Index of Stable Febrile Neutropenia (CISNE), with six explanatory
variables associated with serious complications: Eastern Cooperative Oncology Group perfor-
mance status ⱖ 2 (2 points), chronic obstructive pulmonary disease (1 point), chronic cardiovas-
cular disease (1 point), mucositis of grade ⱖ 2 (National Cancer Institute Common Toxicity Criteria;
1 point), monocytes ⬍ 200 per ␮L (1 point), and stress-induced hyperglycemia (2 points). We
integrated these factors into a score ranging from 0 to 8, which classifies patients into three
prognostic classes: low (0 points), intermediate (1 to 2 points), and high risk (ⱖ 3 points). We
present a multicenter validation of CISNE.
Results
We prospectively recruited 1,133 patients with seemingly stable FN from 25 hospitals. Compli-
cation rates in the training and validation subsets, respectively, were 1.1% and 1.1% in low-, 6.1%
and 6.2% in intermediate-, and 32.5% and 36% in high-risk patients; mortality rates within each
class were 0% in low-, 1.6% and 0% in intermediate-, and 4.3% and 3.1% in high-risk patients.
Areas under the receiver operating characteristic curves in the validation subset were 0.652 (95%
CI, 0.598 to 0.703) for Talcott, 0.721 (95% CI, 0.669 to 0.768) for Multinational Association for
Supportive Care in Cancer (MASCC), and 0.868 (95% CI, 0.827 to 0.903) for CISNE (P ⫽ .002 for
comparison between CISNE and MASCC).
Conclusion
CISNE is a valid model for accurately classifying patients with cancer with seemingly stable
FN episodes.
J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

© 2015 by American Society of Clinical
Oncology INTRODUCTION
0732-183X/15/3399-1/$20.00
Chemotherapy-induced febrile neutropenia (FN) is
DOI: 10.1200/JCO.2014.57.2347
a frequent, potentially life-threatening toxicity that
predisposes patients with cancer to serious infec-
tions and limits the delivery of optimal therapeutic
doses of chemotherapy. The rate of major complica-
tions in the context of FN is approximately 25% to
30%, and mortality is as high as 11% in some patient
groups.1 Overtreatment of low-risk episodes is also a
common and stressful experience for patients, as
well as a burden for health care systems.2 The most
widely validated prognostic tool used to select low-
risk patients with FN is the Multinational Associa-
tion for Supportive Care in Cancer (MASCC) score,
which has been shown to be more accurate than the
Talcott classification.3-5 However, these models are
not specific to patients with solid tumors. In addi-
tion, the ability of the MASCC score to predict seri-
ous complications is not optimal, because they

© 2015 by American Society of Clinical Oncology 1

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Copyright 2015 by American Society of Clinical Oncology
 Carmona-Bayonas et al
occur in up to 9% to 15% of patients predicted to be at low risk.3,6
Thus, it is of interest to develop more precise models to stratify FN
episodes and optimize therapy.
Over the last few years, several randomized clinical trials have dem-
onstrated that oral or ambulatory treatment is a feasible alternative for
low-risk FN.7 However, the validated tools mentioned were not used in
most of these studies as a single decision criterion; rather, therapeutic
management was based on clinical exclusion criteria. Although some
criteria, such as shock and acute organ dysfunction, were similar across
studies,arecentclinicalpracticeguidelinebasedonareviewofpooleddata
fromrandomizedclinicaltrialsassessingoutpatientversusinpatientman-
agement concluded that the best approach to identifying low-risk patients
remains unknown.8 Nonetheless, the application of a set of exclusion
criteria that would preclude patient discharge was recommended, even if
patients were classified as low risk by other methods.
A recent study by our group assessed 692 clinically stable FN
episodes that did not fulfill those generally accepted exclusion criteria.
A relevant rate of serious complications (7%) was observed, even in
the absence of clinical instability.9 Hence, we developed a prognostic
score (Clinical Index for Stable Febrile Neutropenia [CISNE]) for
predicting serious complications in this seemingly low-risk popu-
lation.9 The FINITE (Evaluación de Factores Pronósticos en Fiebre
Neutropénica, Tumor Sólido y Episodios Estables) study was de-
signed to validate the CISNE score and compare its predictive
performance with that of other approaches.
PATIENTS AND METHODS
Patients
Patients were consecutively and prospectively recruited from 24 Spanish
teaching hospitals and one center in Chile from September 2012 to July 2014.
All patients provided written informed consent in accordance with the respec-
tive ethics committee of each institution. Consent could be withdrawn at
any time. Only the first episode occurring in a patient during the study
period was considered.
Patients eligible for inclusion were ambulatory adults (age ⱖ 18 years)
meeting the following definition of FN: fever ⱖ 38°C and neutropenia ⱕ 500
per ␮L (or ⱕ 1,000 per ␮L with expected decrease ⱕ 500 per ␮L). Patients were
required to have a solid tumor treated with mild- or moderate-intensity
chemotherapy. Finally, patients were included if they were judged to be clini-
cally stable within the first 3 hours after diagnosis of FN. Clinical stability was
defined as in the CISNE derivation series9 and included all of the following:
absence of acute organ failure (renal, cardiac, and respiratory) and decompen-
sation of chronic organ insufficiency, absence of septic shock and hypotension
(systolic pressure ⬍ 90 mm/Hg), no known severe infections, and absence of
other serious complications, constituting admission criteria in and of them-
selves (Appendix Table A1, online only).
Patientswereexcludediftheywerenotconsideredtobeclinicallystableatthe
time of assessment or if FN developed during hospitalization for another reason.
Patients treated with high-dose, induction, or intensification chemotherapy for
acute leukemia, bone marrow transplantation, or other induction regimens for
lymphoma were also excluded. Oral and outpatient treatments were allowed ac-
cording to the investigators’ judgment, but an episode was excluded if manage-
ment did not follow Infectious Diseases Society of America clinical guidelines.10
Study Design
Clinical data were obtained from both the patient and the records
generated in the emergency department. The information was gathered
and updated by physicians experienced in cancer supportive care, who
were trained to comply with the study requirements through a Web-based
platform (www.finite.es). On-site and telephone data monitoring were per-
2 © 2015 by American Society of Clinical Oncology
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129.81.226.78
formed at all centers. Missing values for any model explanatory covariates were
not allowed, although all predictors were easily available, and no patients were
excluded for this reason. Even though data collection was not blinded, inves-
tigators were unaware of the CISNE categories.
The main outcome measure was the appearance of major complications
associated with FN episodes in patients considered to be clinically stable. Major
complications were defined as the occurrence of hypotension; acute renal,
respiratory, or heart failure; arrhythmia; major bleeding; delirium; acute ab-
domen; disseminated intravascular coagulation; and other events considered
severe according to the definitions in the study protocol (Appendix Table A1,
online only). The observation period lasted a minimum of 7 days, from the
time of arrival at the emergency department until complete resolution of the
episode. This was defined as the disappearance of all signs of infection, with
recovery from neutropenia (ⱖ 1,500 neutrophils/␮L) and absence of fever for
48 hours. If the patient was discharged early or received ambulatory treatment,
this period also included a home surveillance component.
Derivation of CISNE Score
CISNE is a prognostic model developed from a single-center retrospec-
tive cohort of seemingly clinically stable FN episodes treated between 1996 and
2004.9 The CISNE derivation cohort comprised 692 episodes, with a compli-
cation rate of 7%. The risk prediction model was generated using a nested
case-control design in the aforementioned cohort, using a 1:3 ratio for cases
and controls.11 To derive that model, we used clinical variables routinely
available at the time of first assessment shown to be relevant in FN.9 The
CISNE model included six explanatory variables associated with complica-
tions: Eastern Cooperative Oncology Group performance status ⱖ 2, chronic
obstructive pulmonary disease, chronic cardiovascular disease, mucositis of
grade ⱖ 2 (National Cancer Institute Common Toxicity Criteria), monocytes
⬍ 200 per ␮L, and stress-induced hyperglycemia (Table 1). In this study, we
applied a split-sample method to the FINITE data set to develop a prognostic
score. Approximately two thirds of the episodes were randomly assigned to a
training subset in which ␤ coefficients for CISNE covariates were updated (n ⫽
801), whereas one third were reserved for validation (n ⫽ 332). Both subsets
were compared with respect to baseline characteristics (Table 2). A logistic
regression model was developed for the training subset. Coefficients were
rounded off as integers to simplify the model and obtain the score by a simple
addition. The Hosmer-Lemeshow test was used to analyze the agreement
between predicted and observed probabilities. The overall risk score for a given
individual was the total sum of points, establishing three prognostic categories:
low (0 points), intermediate (1 to 2 points), and high risk (ⱖ 3 points).
Validation of CISNE Score and Comparison With
Other Methods
Performance of the CISNE, Talcott, and MASCC models was evaluated
using a separate validation subset. An ordinal logistic regression was developed
to determine whether random group allocation to the training versus valida-
tion subsets had an effect on the ordered CISNE scores. To test inferential
extensibility, we set up eight partitions corresponding to the eight regions in
which the hospitals of this study were divided by leaving out one region each
Table 1. CISNE Score
Characteristic Points
ECOG PS ⱖ 2 2
SIH 2
COPD 1
Chronic cardiovascular disease 1
Mucositis NCI grade ⱖ 2 1
Monocytes ⬍ 200 per ␮L 1
Abbreviations: CISNE, Clinical Index of Stable Febrile Neutropenia; COPD,
chronic obstructive pulmonary disease; ECOG PS, Eastern Cooperative
Oncology Group performance status; NCI, National Cancer Institute; SIH,
stress-induced hyperglycemia.
JOURNAL OF CLINICAL ONCOLOGY
 Prognostic Classification of Febrile Neutropenia

model cost sensitive.13 The Talcott model was dichotomized into high and low
Table 2. Comparison of Baseline Characteristics in FINITE Study Subsets risk, according to the original description.5 We compared the discriminatory
Training Validation ability of the scales on the basis of their areas under the receiver operating
Subset Subset characteristic curves,12 using the Hanley method,13 and the standard measures
(n ⫽ 801) (n ⫽ 332) of sensitivity, specificity, positive (PPVs) and negative predictive values
Characteristic No. % No. % P (NPVs), and positive (pLR) and negative likelihood ratios (nLRs). We also
constructed a reclassification table for patients with and without complica-
Age ⱖ 65 years 304 38 107 32 NS
tions to calculate the net reclassification improvement.14
Male sex 435 54 178 54 NS
COPD 109 14 42 13 NS
Chronic cardiovascular disease 64 8 22 7 NS
Statistics
ECOG PS ⱖ 2 142 18 56 17 NS
Standard descriptive statistics, including absolute and relative frequencies,
Prophylactic G-CSF 213 27 89 27 NS
means, and standard deviations, were used. We provided 95% CIs when appro-
Previous antibiotics, ⬍ 1 month 136 17 66 20 NS
priateandconsideredasignificancelevelofP⬍.05inallstatisticaltests.Two-tailed
Objective of chemotherapy
P values were calculated. We used the Breslow-Day test to assess the homogeneity
Adjuvant 140 30 103 31 NS
of the odds ratios (ORs) of the dichotomized score across study centers. A forest
Neoadjuvant 137 17 62 19 NS
plot was created using OpenMeta[Analyst] software (Center for Evidence-Based
Palliative 396 44 157 47 NS
Medicine, Brown University, Providence, RI). The likelihood ratio test was applied
Malignant disease
to test heterogeneity among variables of interest. According to previous studies, a
Breast cancer 273 34 118 35 NS
sample size of 1,133 episodes with 152 events was considered sufficient to validate
Lung cancer 170 21 64 19 NS
a model with six covariates.15 By convention, all positive regression coefficients
Esophageal-gastric cancer 53 7 24 7 NS
were associated with the development of complications.
Colorectal cancer 44 5 15 4 NS
Sarcoma 38 5 12 4 NS
RESULTS
Germ cell cancer 17 2 9 3 NS
Lymphoma 17 2 5 1 NS
Tumor stage Baseline Characteristics of Patients
III 223 28 106 32 NS The sample included 1,133 patients (Fig 1). Baseline characteris-
IV 374 47 143 43 NS tics in the two subsets were well balanced (Table 2), although signifi-
MASCC ⱖ 21 (low risk) 667 83 285 86 NS
cant heterogeneity was observed across geographic regions (Appendix
Talcott group IV (low risk) 686 86 279 84 NS
Focus of infection
Table A2, online only). The most frequent types of infection reported
Enteritis 107 13 36 11 NS involved the respiratory tract (n ⫽ 293), with the upper respiratory
Upper respiratory tract 118 15 50 15 NS tract being involved more often than lower respiratory tract. Most
Urinary tract 44 5 23 7 NS patients were treated as inpatients (70%). The mean duration of grade
Bronchitis 87 11 38 11 NS 4 neutropenia was 2.5 days (95% CI, 2.4 to 2.6), whereas fever lasted a
Mucositis 97 12 35 10 NS mean of 1.9 days (95% CI, 1.8 to 2.0). The most frequent empiric
No infectious focus 269 34 115 35 NS
Patient management
Outpatient 89 11 34 10 NS
Early discharge 144 18 71 21 NS
Assessed for eligibility
Inpatient 568 71 228 69 NS (N = 1,543)
Route of antibiotics
Oral 83 10 28 8 NS
Did not meet inclusion criteria (n = 350)
Intravenous 606 76 258 78 NS
Pneumonia (n = 42)
Sequential 110 14 45 14 NS Other serious infection (n = 27)
Neutrophils ⬍ 100 per ␮L 351 44 149 45 NS Shock (n = 121)
Serious complications 107 13 45 14 NS Acute organ failure (n = 45)
Death 17 2 3 1 NS Exacerbated chronic dysfunction (n = 37)
Complications at the onset (n = 73)
Bacteremia 86 11 37 11 NS
Nonadherence to IDSA guidelines (n = 5)
Abbreviations: COPD, chronic obstructive pulmonary disease; ECOG PS,
Eastern Cooperative Oncology Group performance status; FINITE, Evaluación Excluded (n = 60)
de Factores Pronósticos en Fiebre Neutropénica, Tumor Sólido y Episodios Declined to participate (n = 15)
Estables; G-CSF, granulocyte colony-stimulating factor; MASCC, Multinational Missing values (n = 0)
Association for Supportive Care in Cancer; NS, not significant.
Inpatient (n = 16)
Multiple episodes for a single patient (n = 21)
Other reasons (n = 8)

time. Successive logistic regression analyses were applied to each sample, and Eligible episodes of FN
specific scales were constructed in the same manner as previously mentioned. (n = 1,133)
We calculated performance separately over the corresponding left-out subsets
and averaged the results across regions. The linear-by-linear association test Complications (n = 152)
was used to determine whether the risk of complications and mortality corre- Death (n = 20)
sponded to CISNE categories. The MASCC score was evaluated according to
previously reported thresholds. We also re-evaluated the best cutoff points for Fig 1. Flow diagram of FINITE (Evaluación de Factores Pronósticos en Fiebre
the population of seemingly stable patients, so a misclassification cost ratio of Neutropénica, Tumor Sólido y Episodios Estables) study. FN, febrile neutropenia;
5:1 for false-negative versus false-positive results was considered to make the IDSA, Infectious Diseases Society of America.

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129.81.226.78
 Carmona-Bayonas et al

points), 44% as class II (1 to 2 points), and 31% as class III (ⱖ 3

Table 3. Predictors of Serious Complications in Training Subset by Logistic
Regression Analysis (n ⫽ 801)
points), with a comparable risk category distribution in both subsets.
We then evaluated the prognostic performance of the model in
Characteristic ␤ Coefficient OR 95% CI P
the validation subset. The risks of serious complications and death
ECOG PS ⱖ 2 1.89 6.6 3.9 to 11.1 ⬍ .001
rose as the CISNE category increased, with a complication rate of
COPD 0.66 1.9 1.1 to 3.5 .02
Cardiovascular disease 0.81 2.2 1.1 to 4.6 .03
1.1%, 6.2%, and 36% (P ⬍ .001) and mortality rate of 0%, 0%, and
Mucositis NCI grade ⱖ 2 0.84 2.3 1.3 to 3.9 ⬍ .001 3.1% for classes I, II, and III (P ⫽ .02), respectively. Consequently, the
Monocytes ⬍ 200 per ␮L 1.08 2.9 1.7 to 4.9 ⬍ .001 OR for complications between classes III and I to II was 12.7 (95%, CI,
SIH 1.56 4.7 2.9 to 7.7 ⬍ .001 5.9 to 27.1). With a cutoff of ⱖ 3 points, CISNE showed good discrim-
Abbreviations: COPD, chronic obstructive pulmonary disease; ECOG PS, inatory power to predict major complications, with the following
Eastern Cooperative Oncology Group performance status; NCI, National parameters: sensitivity, 77.7%; specificity, 78.4%; PPV, 36.1%; NPV,
Cancer Institute; OR, odds ratio; SIH, stress-induced hyperglycemia.
95.7%; pLR, 3.6; and nLR, 0.28. Of note, the Breslow-Day test indi-
cated homogeneity of the OR for complications across the population
(␹2 ⫽ 13.1; P ⫽ .067; Appendix Fig A1, online only). Different data
splits based on geographic distribution did not reveal substantial
antibiotic treatments were piperacillin and tazobactam (51%), amoxi- changes with respect to overall classification performance (Appendix
cillin and clavulanate plus ciprofloxacin (14%), cefepime (9%), and Tables A3 and A4, online only).
meropenem (10%). Combination therapy with either aminoglyco-
sides or glycopeptides was used in 12% and 4%, respectively. Comparison of CISNE, MASCC, and Talcott Scales
We compared the accuracy of the three scales and calculated the
Complications and Mortality optimal cutoff value of the MASCC index for this population. Accord-
The primary end point (serious complications) occurred in 152 ing to MASCC ⱖ 21 and Talcott IV criteria, 84% and 85% of the
patients (13.4%; 95% CI, 11.5% to 15.5%), and 20 patients (1.8%; episodes, respectively, were classified as low risk. With that standard
95% CI, 1.1% to 2.7%) died. The most common complications were cutoff, the MASCC score (⬍ 21 points) exhibited the following pre-
shock (7%), acute respiratory failure (6%), acute renal dysfunction dictive parameters to identify high-risk patients: sensitivity, 34.8%;
(3%), delirium (2%), clinically relevant arrhythmia (1%), acute heart specificity, 86.9%; PPV, 29.3%; NPV, 89.6%; pLR, 2.67; and nLR, 0.75.
dysfunction (1%), acute abdomen (1%), and bleeding (0.5%). The optimal criterion for high risk was ⬍ 24 points according to the ad
A logistic regression analysis was conducted on the training sub- hoc cost-sensitive analysis. However, the performance of the CISNE
set (Table 3). CISNE demonstrated good calibration (Hosmer- score remained higher with respect to the MASCC-adjusted cutoff
Lemeshow goodness-of-fit test: ␹2 ⫽ 1.1; P ⫽ .9). The ordinal logistic value of ⬍ 24, which revealed the following: sensitivity, 64.4%; speci-
regression analysis of the CISNE scores in the training versus valida-
tion subsets showed that both groups were comparable (␹2 ⫽ 3.6; P ⫽
.058). As shown in Table 4, 24% of patients were classified as class I (0
100

Table 4. Comparison of Complications, Mortality, and Bacteremia According 80

to CISNE Category in FINITE Training and Validation Subsets

Training Subset Validation Subset

(n ⫽ 801) (n ⫽ 332)
Risk Category 60
Sensitivity

(class) % 95% CI % 95% CI P

Distribution
I (0 points) 23.2 20.4 to 26.2 27.4 22.8 to 32.4 NS
II (1-2 points) 44.9 41.5 to 48.4 43.4 38.1 to 48.7 NS 40
III (ⱖ 3 points) 31.8 28.7 to 35.1 29.2 24.5 to 34.3 NS
Complications
I (0 points) 1.1 0.3 to 3.8 1.1 0.1 to 5.9 NS
20
II (1-2 points) 6.1 4.0 to 9.0 6.2 3.3 to 11.4 NS CISNE score
III (ⱖ 3 points) 32.5 27.0 to 38.5 36.0 27.2 to 46.0 NS MASCC score
Mortality Talcott classification
I (0 points) 0.0 0.0 to 2.0 0.0 0.0 to 4.0 NS
II (1-2 points) 1.6 0.7 to 3.5 0.0 0.0 to 2.6 NS 0 20 40 60 80 100
III (ⱖ 3 points) 4.3 2.4 to 7.5 3.1 1.0 to 8.7 NS
Bacteremia 100-Specificity
I (0 points) 3.2 1.4 to 6.8 9.1 4.8 to 16.3 .02
II (1-2 points) 9.7 7.1 to 13.2 9.0 5.3 to 14.8 NS Fig 2. Receiver operating characteristic (ROC) curves of Clinical Index for Stable
Febrile Neutropenia (CISNE), Multinational Association for Supportive Cancer in
III (ⱖ 3 points) 17.6 13.4 to 22.8 15.5 9.6 to 23.9 NS
Cancer (MASCC), and Talcott models for predicting serious complications in valida-
Abbreviations: CISNE, Clinical Index of Stable Febrile Neutropenia; FINITE, tion subset (n ⫽ 332). Areas under ROC curves were 0.652 (95% CI, 0.598 to 0.703)
Evaluación de Factores Pronósticos en Fiebre Neutropénica, Tumor Sólido y for Talcott, 0.721 (95% CI, 0.669 to 0.768) for MASCC, and 0.868 (95% CI, 0.827 to
Episodios Estables; NS, not significant. 0.903) for CISNE, with P ⫽ .0026 for comparison between CISNE and MASCC and
P ⫽ .27 for comparison between MASCC and Talcott.

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 Prognostic Classification of Febrile Neutropenia
ficity, 68.6%; PPV, 24.1%; NPV, 92.6%; pLR, 2.05; and nLR, 0.52. The
comparison of areas under the receiver operating characteristic curves
is shown in Figure 2. Appendix Table A5 (online only) is a reclassifi-
cation table comparing CISNE and MASCC. The net reclassification
improvement of CISNE over MASCC was 32% in the overall sample.
DISCUSSION
Several analyses have identified prognostic factors in patients with FN,
but until now, to our knowledge, no study had addressed the develop-
ment and validation of a prognostic score in a large cohort of outpa-
tients with solid tumors and seemingly stable FN episodes. Here we
demonstrate the ability of the CISNE prognostic score to discriminate
the risk of developing severe complications in patients with these
characteristics9 and its superior performance in comparison with the
MASCC model in this setting.
The rationale for targeting the subgroup of clinically stable pa-
tients was based on clinicians’ practical interest in obtaining useful
tools to support their clinical decisions. In particular, we observed that
the identification of patients who are clearly unwell is easy by means of
a basic clinical assessment. Additional prognostic scales are not re-
quired to change medical management decisions after applying sets of
exclusion criteria in this type of high-risk patients.8 In contrast, the
challenge is to identify seemingly healthier patients with the potential,
albeit low risk, for developing serious complications. Therefore, a prog-
nostic score such as CISNE might clarify some of the remaining prognos-
tic uncertainty in this group in a clinically meaningful manner.
Seemingly stable patients represent a numerically important
group. Because all patients receiving chemotherapy are instructed to
go to the hospital on the development of fever, most seek emergency
care in the early stages of infection, before complications arise.9 Hence,
this population is enriched with patients with mild infections who
may be eligible for outpatient management.8,10 The mortality rate in
the FINITE data set was lower than expected for other cohorts with no
selection for clinical stability1,16 but similar to those found in other
low-risk cohorts.3 In contrast, the rate of complications (13%) was
intermediate between low- and high-risk groups.3 The failure of ex-
clusion criteria to predict the development of complications can be
explained by the paucity of inflammatory response resulting from im-
munosuppression, which may reduce our ability to detect severe infec-
tions at first assessment. Although our eligibility criteria were similar to
those applied in clinical trials dealing with outpatient therapy, the FINITE
set showed a higher rate of clinical deterioration in comparison with these
studies.17-22 As a possible explanation, we hypothesize that not all eligible
patients are typically enrolled onto clinical trials, because of physician or
patient refusal, and that irregular inclusion of eligible patients could bias
the results by making de facto selection criteria even more stringent than
declared. In such settings, multicenter, observational studies based on
clinical practice with large sample sizes remain a valuable source of prog-
nostic information.
The predictive performance of the MASCC score was low in our
data set, probably because its discriminatory ability is linked to the
population in which the model was validated, which differed from this
cohort of stable patients with solid tumors and mild- or moderate-
intensity chemotherapy.23 Although we evaluated the performance of
the MASCC score at different thresholds, we found that raising the
cutoff (from 21 to 24 points) did not substantially improve the prediction
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over and above the CISNE score. These findings are a warning of the risks
of applying models to populations that differ from those in which they
were originally validated. Therefore, the introduction of the MASCC
scoreasasecondevaluationstepinagroupofclinicallystablepatientswith
FN does not seem to be an appropriate strategy for identifying high-risk
individuals. In contrast, the CISNE score discriminated between patients
at low, intermediate, and high risk for complications, bacteremia, and
death. Hence, a two-step combination of a set of exclusion criteria plus a
validated triage-friendly scale such as CISNE rendered better prognostic
stratification than those of the approaches currently used.
The results of our research are mainly applicable to prevent
premature discharge of patients with cancer beginning inpatient man-
agement. In light of our data, we suggest that patients experiencing
episodes classified as CISNE class III (ⱖ 3 points) should not be sent
home until they are seen to be truly stable and blood cultures have
been examined. Nonetheless, well-conducted clinical trials are needed
to confirm that these prognostic categories can be successfully corre-
lated with therapeutic classes. Further improvement could be
achieved by taking into consideration specific infections and tumor
status, although infrequent sources of risk and local microbiologic
issues may still be important in some cases.
Several points should be taken into account when considering the
generalizability of the model. Given the low number of patients with
lymphoma (n ⫽ 22), more experience on this subgroup is required. The
delay from symptom onset until contact with the health care system was
not controlled. We tested whether the CISNE score could be generalized
and used in other regions or settings. Although there were slight variations
in prevalence of chronic conditions across centers because of local or
epidemiologic issues, CISNE proved to be robust with respect to these
variations (Appendix Tables A2 and A4, online only). Our analysis sug-
gests that the individual weight of infrequent CISNE covariates, such as
those representing chronic conditions (eg, chronic obstructive pulmo-
nary disease or cardiovascular diseases), may be sensitive to changes in
prevalence (Appendix Table A3, online only), which should be taken into
account when interpreting the model. Other limitations include the sam-
pling constraint in the original data set, consisting of a retrospective,
single-center analysis of relatively few patients (n ⫽ 692). Although the
investigators recording the data were unaware of the CISNE categories,
unblinded data capture may have introduced bias into the assessment of
the models. Only 10% of the FINITE sample came from the same center
in which the CISNE model was originally developed.
In conclusion, patients with FN considered to be clinically stable can
be stratified into three groups with markedly different clinical courses
based on the validated CISNE score. The CISNE score may be considered
a new standard of risk classification to help clinicians to make safer indi-
vidualized treatment decisions, including for outpatient therapy.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Alberto Carmona-Bayonas, Paula
Jiménez-Fonseca, Juan Virizuela Echaburu, Maite Antonio, Carme Font,
© 2015 by American Society of Clinical Oncology 5
 Carmona-Bayonas et al

Mercè Biosca, Avinash Ramchandani, Jerónimo Martínez, Jorge
Hernando Cubero, Eva Martínez de Castro, Ismael Ghanem, Carmen
Beato, Ana Blasco, Marcelo Garrido, Yaiza Bonilla, Rebeca Mondéjar,
María Ángeles Arcusa Lanza, Isabel Aragón Manrique, Elena Sevillano,
Eduardo Castañón, Elena Gallardo Martín, Quionia Pérez Armillas,
Francisco Ayala de la Peña
Financial support: Juan Virizuela Echaburu
Administrative support: Alberto Carmona-Bayonas, Juan Virizuela
Echaburu, Maite Antonio
Provision of study materials or patients: Alberto Carmona-Bayonas,
Juan Virizuela Echaburu, Maite Antonio
Collection and assembly of data: Alberto Carmona-Bayonas, Paula
Jiménez-Fonseca, Maite Antonio, Carme Font, Mercè Biosca, Avinash
Ramchandani, Jerónimo Martínez, Jorge Hernando Cubero, Javier
Espinosa, Ismael Ghanem, Carmen Beato, Ana Blasco, Marcelo Garrido,
Rebeca Mondéjar, María Ángeles Arcusa Lanza, Isabel Aragón Manrique,
Aránzazu Manzano, Elena Sevillano, Eduardo Castañón, Mercé Cardona,
Elena Gallardo Martín, Quionia Pérez Armillas
Data analysis and interpretation: Alberto Carmona-Bayonas, Paula
Jiménez-Fonseca, Juan Virizuela Echaburu, Carme Font, Mercè Biosca,
Avinash Ramchandani, Jerónimo Martínez, Jorge Hernando Cubero,
Javier Espinosa, Eva Martínez de Castro, Ismael Ghanem, Carmen Beato,
Ana Blasco, Marcelo Garrido, Rebeca Mondéjar, María Ángeles Arcusa
Lanza, Isabel Aragón Manrique, Elena Sevillano, Eduardo Castañón,
Elena Gallardo Martín, Quionia Pérez Armillas, Fernando Sánchez
Lasheras, Francisco Ayala de la Peña
Manuscript writing: All authors
Final approval of manuscript: All authors

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Affiliations
Alberto Carmona-Bayonas and Francisco Ayala de la Peña, Hospital Universitario Morales Meseguer; Jerónimo Martínez, Hospital
Universitario Virgen de la Arrixaca, Murcia; Paula Jiménez-Fonseca, Hospital Universitario Central de Asturias, Oviedo; Juan Virizuela
Echaburu, Hospital Universitario Virgen Macarena; Carmen Beato, Hospital Nisa Aljarafe, Seville; Maite Antonio, Institut Català d’Oncologia
Duran i Reynals; Carme Font, Hospital Universitario Clínic; Mercè Biosca, Hospital Universitario Vall d’Hebron; María Ángeles Arcusa
Lanza, Consorci Sanitari de Terrassa, Barcelona; Avinash Ramchandani, Hospital Universitario de Las Palmas, Las Palmas; Jorge Hernando
Cubero, Hospital Universitario Miguel Servet, Zaragoza; Javier Espinosa, Hospital General Universitario de Ciudad Real, Ciudad Real; Eva
Martínez de Castro, Hospital Universitario Marqués de Valdecilla, Santander; Ismael Ghanem, Hospital Universitario La Paz; Rebeca
Mondéjar, Hospital Virgen de la Luz de Cuenca; Aránzazu Manzano, Hospital Universitario Clínico San Carlos, Madrid; Ana Blasco, Hospital
General Universitario de Valencia, Valencia; Yaiza Bonilla, Hospital de Santa Lucía, Cartagena; Isabel Aragón Manrique, Hospital Juan
Ramón Jiménez, Huelva; Elena Sevillano, Hospital Universitario Son Espases, Palma de Mallorca; Eduardo Castañón, Clínica Universitaria
Navarra, Navarre; Mercé Cardona, Hospital de Tortosa Verge de la Cinta, Tarragona; Elena Gallardo Martín, Complejo Universitario de
Pontevedra, Pontevedra; Quionia Pérez Armillas, Hospital Universitario de Valladolid, Valladolid; Fernando Sánchez Lasheras, University of
Oviedo, Gijón, Spain; and Marcelo Garrido, Universidad Católica Pontificia de Chile, Santiago de Chile, Chile.
■ ■ ■

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 Prognostic Classification of Febrile Neutropenia

GLOSSARY TERMS

febrile neutropenia: symptoms include fever and a decrease test. The area under the curve is a measure of the accuracy of the test.
in the number of neutrophils in the blood. A low neutrophil An area of 1.0 represents a perfect test (all true positives), whereas an
count increases the risk of infection. area of 0.5 represents a worthless test.

logistic regression model: a multivariable prediction risk score: a simplified version of a prognostic model, in which scores
model in which the log of the odds of a time-fixed outcome event are assigned to each risk factor (eg, on the basis of rounded regression
or other binary outcome is related to a linear equation. coefficients).

receiver operating characteristic (ROC) curves: split-sample validation: a method used for internal validation in
curves that plot the true-positive rate (sensitivity) against the which the sample is split into two portions; one is used as a training set
false-positive rate (1-specificity) for different cutoff levels of a and the other as a test set.

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 Carmona-Bayonas et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Prediction of Serious Complications in Patients With Seemingly Stable Febrile Neutropenia: Validation of the Clinical Index of Stable Febrile Neu-
tropenia in a Prospective Cohort of Patients From the FINITE Study
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Alberto Carmona-Bayonas Marcelo Garrido
No relationship to disclose No relationship to disclose
Paula Jiménez-Fonseca Yaiza Bonilla
No relationship to disclose No relationship to disclose
Juan Virizuela Echaburu Rebeca Mondéjar
No relationship to disclose No relationship to disclose
Maite Antonio María Ángeles Arcusa Lanza
No relationship to disclose No relationship to disclose
Carme Font Isabel Aragón Manrique
No relationship to disclose
No relationship to disclose
Mercè Biosca
Aránzazu Manzano
No relationship to disclose
No relationship to disclose
Avinash Ramchandani
No relationship to disclose Elena Sevillano
No relationship to disclose
Jerónimo Martínez
No relationship to disclose Eduardo Castañón
No relationship to disclose
Jorge Hernando Cubero
No relationship to disclose Mercé Cardona
No relationship to disclose
Javier Espinosa
No relationship to disclose Elena Gallardo Martín
No relationship to disclose
Eva Martínez de Castro
No relationship to disclose Quionia Pérez Armillas
No relationship to disclose
Ismael Ghanem
No relationship to disclose Fernando Sánchez Lasheras
No relationship to disclose
Carmen Beato
No relationship to disclose Francisco Ayala de la Peña
Ana Blasco No relationship to disclose
No relationship to disclose

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 Prognostic Classification of Febrile Neutropenia

Appendix

Table A1. Definitions of Complications and Other Variables

Variable Definition
Clinical stability All of the following within first 3 hours of first assessment: absence of acute organ failure (renal, cardiac, respiratory) or
decompensation of chronic insufficiency, absence of septic shock or hypotension (systolic pressure ⬍ 90 mm/Hg),
no known severe infections, and absence of other serious complications constituting admission criteria by
themselves (pulmonary thromboembolism, arrhythmias, disseminated intravascular coagulation, bleeding)
Major infections Pneumonia, empyema, peritonitis, cellulitis ⬎ 5 cm, suspected typhlitis, enteritis NCI grade 3 to 4, appendicitis,
cholecystitis or other complicated abdominal infections, meningitis, encephalitis, endocarditis, and pyelonephritis
Hypotension Persistent systolic blood pressure ⬍ 90 mm/Hg requiring inotropes or aggressive fluid resuscitation
Acute respiratory failure Oxygen saturation ⬍ 90%, partial pressure of oxygen in arterial blood ⬍ 60 mm/Hg, or partial pressure of carbon
dioxide in arterial blood ⱖ 45 mm/Hg
Acute renal failure Increase in creatinine ⱖ 0.3 mg/dL within 48 hours, increase in creatinine to ⱖ 1.5 ⫻ baseline within prior 7 days, or
urine volume ⬍ 0.5 mL/kg per hour for 6 hours
Acute heart failure Rapid onset of dyspnea, pulmonary edema, and oxygen desaturation requiring urgent therapy
Arrhythmias Arrhythmias considered as complications whenever they alter cardiovascular stability
Delirium Acute, fluctuating alteration of mental state with cognitive impairment
Major bleeding Episodes associated with death, occurring in critical localization (intracranial, intraspinal, intraocular, retroperitoneal, or
pericardial), or associated with reduction in hemoglobin values ⱖ 2 g/dL or bleeding that requires transfusion of two
units of concentrated RBCs
Acute abdomen Acute abdomen defined as syndrome because of variety of pathogenic conditions that require urgent medical or
surgical management
COPD Emphysema, chronic bronchitis, decrease in forced expiratory volumes or need for oxygen therapy, corticosteroids, or
bronchodilators
Chronic cardiovascular disease Chronic heart conditions (eg, cor pulmonale, heart failure, cardiomyopathy, hypertensive heart disease, arrhythmias,
valvular heart disease, or other structural malformations) at risk of acute exacerbations in FN setting; single isolated
episodes of atrial fibrillation in past were not considered here as chronic cardiovascular diseases
SIH Glucose ⱖ 121 mg/dL or ⱖ 250 mg/m2 in diabetic patient (or in patient receiving corticosteroids)
Mucositis NCI grade ⱖ 2 At least presence of patchy ulcerations or pseudomembranes, or moderate pain with modified diet indicated

Abbreviations: COPD, chronic obstructive pulmonary disease; FN, febrile neutropenia; NCI, National Cancer Institute; SIH, stress-induced hyperglycemia.

Table A2. Distribution of Covariates and Other Baseline Characteristics by Hospitals or Regions (N ⫽ 1,133)
HMM ICO-DR NSH HCB HIGC CMH SESH Other

Characteristic No. % No. % No. % No. % No. % No. % No. % No. % P

Age ⱖ 65 years 72 35 45 31 67 35 55 38 29 41 27 46 43 38 73 36 NS
Male sex 84 40 74 51 106 56 64 44 26 37 27 46 42 37 97 48 .01
ECOG PS ⱖ 2 41 20 39 27 33 17 21 15 11 15 5 8 16 14 32 16 .03
COPD 22 11 18 12 34 18 25 17 13 21 6 10 7 6 24 12 .01
Cardiovascular disease 15 7 14 10 18 9 10 7 4 6 7 12 3 3 15 7 NS
Mucositis NCI grade ⱖ 2 37 18 31 21 39 21 14 9 15 21 12 20 22 19 37 18 NS
Monocytes ⬍ 200 per ␮L 101 49 62 42 90 48 86 60 26 36 28 47 43 38 101 50 .01
SIH 56 27 26 18 58 31 53 37 34 48 21 36 38 34 65 32 .01

Abreviations: CMH, Castilla-Madrid hospitals; COPD, chronic obstructive pulmonary disease; ECOG PS, Eastern Cooperative Oncology Group performance status;
HCB, Hospital Clínic Barcelona; HIGC, Hospital Insular de Gran Canaria; HMM, Hospital Morales Meseguer; ICO-DR, Instituto Catalán de Oncología Duran i Reynals;
NCI, National Cancer Institute; NS, not significant; NSH, Northern Spain Hospitals; SESH, Southeastern Spain Hospitals; SIH, stress-induced hyperglycemia.

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 Carmona-Bayonas et al

Table A3. Estimated ␤ Coefficients and P Values for Covariates in Each Geographic Partition
1 2 3 4 5 6 7 8

Characteristic ␤ P ␤ P ␤ P ␤ P ␤ P ␤ P ␤ P ␤ P
Site left out HMM ICO-DR NSH HCB HIGC CMH SESH Other
ECOG PS ⱖ 2 1.72 ⬍ .001 2.16 ⬍ .001 2.11 ⬍ .001 2.04 ⬍ .001 1.81 ⬍ .001 1.87 ⬍ .001 1.88 ⬍ .001 2.04 ⬍ .001
COPD 0.56 .05 0.98 ⬍ .001 0.35 .2 0.92 .001 0.85 .001 0.73 .004 0.75 .004 0.74 .008
Cardiovascular disease 1.06 .003 0.84 .01 0.78 .02 1.01 .002 0.96 .003 0.85 .009 0.83 .009 1.13 .001
Mucositis NCI grade ⱖ 2 1.15 ⬍ .001 1.21 ⬍ .001 0.46 .09 1.18 ⬍ .001 1.06 ⬍ .001 0.98 ⬍ .001 1.03 ⬍ .001 1.05 ⬍ .001
Monocytes ⬍ 200 per ␮L 1.10 ⬍ .001 0.97 ⬍ .001 1.11 ⬍ .001 0.81 ⬍ .001 1.05 ⬍ .001 0.99 ⬍ .001 1.04 ⬍ .001 0.94 ⬍ .001
SIH 1.71 ⬍ .001 1.45 ⬍ .001 1.06 ⬍ .001 1.53 ⬍ .001 1.54 ⬍ .001 1.48 ⬍ .001 1.46 ⬍ .001 1.68 ⬍ .001

NOTE. Different region is left out each time, running logistic regression analysis on remaining cases.
Abbreviations: CMH, Castilla-Madrid hospitals; COPD, chronic obstructive pulmonary disease; ECOG PS, Eastern Cooperative Oncology Group performance status;
HCB, Hospital Clínic Barcelona; HIGC, Hospital Insular de Gran Canaria; HMM, Hospital Morales Meseguer; ICO-DR, Instituto Catalán de Oncología Duran i Reynals;
NCI, National Cancer Institute; NSH, Northern Spain Hospitals; SESH, Southeastern Spain Hospitals; SIH, stress-induced hyperglycemia.

Table A4. Comparative Performance of Logistic Regression Models on Eight Left-Out Subsets Representing Geographic Partitions

Partition Region No. of Patients Accuracy (%)ⴱ Sensitivity (%)† Specificity (%)‡ AUC NRI
1 HMM 208 78.3 73.5 79.3 0.851 27.5
2 ICO-DR 146 78.7 87.5 78.3 0.876 67.0
3 NSH 189 84.6 86 84.2 0.906 34.5
4 HCB 144 69.4 72 68.9 0.781 27.6
5 HIGC 71 67.6 85.7 65.6 0.770 59.9
6 CMH 59 81.3 100 79.6 0.970 48.9
7 SESH 113 77.8 72.7 78.4 0.807 33.7
8 Other 203 70.4 63.2 71.2 0.764 19.9
Mean 76.0 80.1 75.6 0.840 39.8
SD 6.1 11.7 6.3 0.07 16.7

Abbreviations: AUC, area under receiver operating characteristic curve; CMH, Castilla-Madrid hospitals; HCB, Hospital Clínic Barcelona; HIGC, Hospital Insular de
Gran Canaria; HMM, Hospital Morales Meseguer; ICO-DR, Instituto Catalán de Oncología Duran i Reynals; NRI, net reclassification improvement; NSH, Northern
Spain Hospitals; SD, standard deviation; SESH, Southeastern Spain Hospitals.
ⴱ
Accuracy ⫽ (true positive ⫹ true negative)/total population.
†Sensitivity ⫽ true positive/total with complications.
‡Specificity ⫽ true negative/patients without complications.

Table A5. Reclassification Table Comparing CISNE and MASCC Scores (N ⫽ 1,133)
CISNE Score Category (points)

Low or Intermediate
Risk (⬍ 3) High Risk (ⱖ 3) Total

MASCC Score (points) No. % No. % No. %

Patients without complications
ⱖ 21 (low risk) 684 80 169ⴱ 20ⴱ 853 100
⬍ 21 (high risk) 63† 49† 65 51 128 100
Total 747 76 234 24 981 100
Patients with complications
ⱖ 21 (low risk) 30 30 69† 70† 99 100
⬍ 21 (high risk) 4ⴱ 8ⴱ 49 92 53 100
Total 34 22 118 78 152 100

NOTE. Overall net reclassification improvement, 32%.

Abbreviations: CISNE, Clinical Index of Stable Febrile Neutropenia; MASCC, Multinational Association for Supportive Care in Cancer.
ⴱ
Episodes incorrectly reclassified when applying CISNE score.
†Episodes correctly reclassified when applying CISNE score.

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 Prognostic Classification of Febrile Neutropenia

Regions Estimate 95% CI Events/CHR Events/CLR

HMM 10.648 4.571 to 24.803 25/61 9/147
ICO-DR 25.200 2.983 to 212.900 7/37 1/109
NSH 32.978 12.492 to 87.058 37/60 6/129
HCB 5.699 2.192 to 14.816 18/55 7/89
HIGC 11.455 1.296 to 101.223 6/28 1/43
CMH 41.609 2.141 to 808.689 5/16 0/43
SESH 9.697 2.371 to 39.651 8/30 3/83
Other 4.237 1.582 to 11.349 12/65 7/138
Overall 10.884 6.055 to 19.565 118/352 34/781
(i2 = 40%; P = .112)

1.2 2.39 5.98 10.88 23.92 59.81 119.62 239.24 598.11 900.69

Odds Ratio (log scale)

Fig A1. Forest plot showing results on prognostic value of Clinical Index for Stable Febrile Neutropenia (CISNE) score by hospital or region (N ⫽ 1,133). Centers with
⬍ 30 patients were combined by homogeneity of practice or geographic proximity. Breslow-Day test for homogeneity: ␹2 ⫽ 13.1; P ⫽ .067. CHR, CISNE high risk
(ⱖ 3 points); CLR, CISNE low risk (⬍ 3 points); CMH, Castilla-Madrid hospitals; HCB, Hospital Clínic Barcelona; HIGC, Hospital Insular de Gran Canaria; HMM, Hospital
Morales Meseguer; ICO-DR, Instituto Catalán de Oncología Duran i Reynals; NSH, Northern Spain Hospitals; SESH, Southeastern Spain Hospitals.

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