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Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review

Critical Reviews in Oncology/Hematology


Neutropenia with fever (febrile neutropenia [FN]) is a serious consequence of myelosuppressive chemotherapy that usually results in hospitalization and the need for intravenous antibiotics. FN may result in dose reductions, delays, or even discontinuation of chemotherapy, which, in turn, may compromise patient outcomes. It is important to identify which patients are at high risk for developing FN so that patients can receive optimal chemotherapy while their risk for FN is appropriately managed. A systematic review of the literature was performed to gain a comprehensive and updated understanding of FN risk factors. Older age, poor performance status, advanced disease, certain comorbidities, low baseline blood cell counts, low body surface area/body mass index, treatment with myelosuppressive chemotherapies, and specific genetic polymorphisms correlated with the risk of developing FN. Albeit many studies have analyzed FN risk factors, there are several limitations, including the retrospective nature and small sample sizes of most studies.

Keywords: Febrile neutropenia, Risk factor, Cancer, Chemotherapy.

1. Introduction

Chemotherapy-induced neutropenia is a common and serious clinical consequence of myelosuppressive chemotherapy. Severe neutropenia may be complicated by fever, or febrile neutropenia (FN), which often results in hospitalization and the administration of empiric broad-spectrum antibiotics. FN has been associated with considerable morbidity, mortality, and costs [1], [2], [3], and [4]. Chemotherapy-induced neutropenia and FN are also important dose-limiting side effects of myelosuppressive chemotherapy that often lead to chemotherapy reductions or treatment delays in subsequent cycles, potentially compromising treatment outcomes [5] and [6].

Chemotherapy regimens have been classified as having a high, intermediate, or low risk of developing FN based on prospective clinical trials of selected patients with variable capture of treatment-related toxicities including neutropenia and FN [7] . Such data have been difficult to evaluate as patients eligible for clinical trials are often highly selected and hematologic toxicities are often underreported. In addition, historically very few chemotherapy clinical trials report the delivered chemotherapy dose intensity which can vary greatly and has a direct influence on rates of toxicity [7] .

Current guidelines state that chemotherapy regimens with >20% FN rate in clinical trials of chemotherapy-naïve patients are considered high risk [8], [9], and [10]. Most regimens used for the treatment of adult solid malignancies are rated as intermediate risk for FN based on previous clinical trials. However, clinical practice guidelines recognize that patient risk factors may elevate FN risk and recommend the assessment of risk factors in estimating the overall risk of FN [8], [9], and [10]. Furthermore, the guidelines recognize older age (particularly >65 years), previous chemotherapy or radiotherapy, pre-existing neutropenia or tumor involvement in the bone marrow, poor performance status, comorbidities (e.g., renal or liver dysfunction), and pre-existing conditions (e.g., infection) as risk factors for developing severe neutropenia [8] . Various studies have attempted to identify risk factors and develop predictive models for chemotherapy-induced neutropenia and its complications, as previously described in a review by Lyman et al. [11] . Since this systematic review was published in 2005, other reports have been published on risk factors for FN in patients with cancer receiving chemotherapy.

In this report, we describe the results of a systematic review of the literature in order to provide a more updated understanding of the risk factors associated with FN. An exhaustive search of the PubMed and Embase databases was undertaken for articles in English published between 2002 and 2012 that reported risk factors for FN. Search terms included neutropenia, agranulocytosis, FN, severe neutropenia, grade 3/4 neutropenia, risk, model(s), prediction, predictive, logistic, leukemia (lymphocytic, chronic, B-cell), lymphoma, non-Hodgkin lymphoma (NHL), cancer, neoplasm(s), carcinoma, malignancy, malignancies, metastasis, metastases, tumor, and chemotherapy. Selected studies reported univariate and/or multivariate analyses of FN risk factors in patients receiving systemic cancer chemotherapy. Reviews, meta-analyses, and case reports were excluded. While various definitions of FN were used, FN was commonly defined as an absolute neutrophil count (ANC) <1000/μL with a temperature >38 °C. Studies that reported on risk factors for hospitalization for FN were also included.

2. Risk factors for Febrile Neutropenia

Risk factors for FN can be classified based on patient-, treatment-, disease-, and genetic characteristics. A total of 31 studies were identified ( Fig. 1 ). Eight studies reported univariate results only ( Table 1 ), four reported multivariate results only ( Table 2 ), and 16 reported on both ( Table 3 ). Three additional studies were identified that reported on genetic markers associated with FN risk ( Table 4 ).


Fig. 1 Selection of studies included in the systematic review.

Table 1 Studies reporting univariate results for FN risk factors.

Study citation Study type Malignancy Chemotherapy Factors associated with FN risk
Crawford et al. (2005) [23] Prospective Lung CAE Female sex
Hansson et al. (2012) [42] Retrospective Breast Docetaxel Rapid neutrophil decline, high drug sensitivity a
Hurria et al. (2005) [30] Retrospective Breast CMF, AC, or AC-T Decrease in WBC, ANC, or hemoglobin levels from cycle 1 to cycle 2
Jenkins et al. (2012) [28] Retrospective Breast TAC Low pretreatment ANC and ALC
Jenkins et al. (2009) [27] Retrospective Breast FEC Low pretreatment ANC, WBC, or platelet count
Meyerhardt et al. (2004) [36] Secondary analysis of prospective data Colorectal Irinotecan None identified
Phippen et al. (2011) [29] Retrospective Gynecologic Various High pretreatment PG-SGA score, low pretreatment albumin or hemoglobin levels
Sharma et al. (2006) [45] Retrospective Ovarian Various Radical procedure, advanced disease stage

a Based on the myelosuppression time course model parameters EC50 and mean transit time.

AC, doxorubicin/cyclophosphamide; AC-T, doxorubicin/cyclophosphamide followed by paclitaxel; ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CAE, cyclophosphamide/doxorubicin/etoposide; CMF, cyclophosphamide/methotrexate/fluorouracil; FEC, 5-fluorouracil/epirubicin/cyclophosphamide; PG-SGA, patient-generated subjective global assessment; TAC, docetaxel/doxorubicin/cyclophosphamide; WBC, white blood count.

Table 2 Studies reporting multivariate results for FN risk factors.

Study citation Study type Malignancy Chemotherapy Factors associated with FN risk
Hershman et al. (2009) [41] Retrospective Lymphoma and various solid tumors Various ≥1 myelosuppressive drug, ≥3 chemotherapy drugs, CSF primary prophylaxis a
Hosmer et al. (2011) [25] Retrospective Various solid tumors Various Cancer type (lung or colon), b advanced disease stage, increasing number of comorbidities, chemotherapy <1 month from diagnosis
Pettengell et al. (2009) [14] Subgroup analysis of prospective data NHL CHOP FN in cycle 1: older age, increasing planned cyclophosphamide or etoposide dose, previous chemotherapy, recent infection, baseline albumin <35 g/L, CSF prophylaxis, a higher weight a

FN in any cycle: older age, increasing planned cyclophosphamide, etoposide, or cytarabine dose, recent infection, CSF prophylaxis, a higher weight, a baseline ANC <3 × 109 L–1, baseline WBC <5 × 109 L–1, baseline alkaline phosphatase >250 IU/mL, cardiovascular comorbidity
Salar et al. (2012) [12] Retrospective NHL R-CHOP FN occurrence model: older age, poorer performance status, lower baseline hemoglobin, no CSF use

Physician-assessment model for ≥20% FN risk: advanced disease stage, older age, poorer performance status, baseline hemoglobin <12 g/dL

a Reduced FN risk was observed.

b Breast cancer was used as the reference.

CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; CSF, colony-stimulating factor; NHL, non-Hodgkin lymphoma; R, rituximab.

Table 3 Studies reporting univariate and multivariate results for FN risk factors.

Study citation Study type Malignancy Chemotherapy Factors associated with FN risk
Alexandre et al. (2007) [21] Prospective Various solid tumors Docetaxel Univariate: cancer type (lung), poor performance status, low baseline lymphocyte count, docetaxel exposure, midazolam concentration

Multivariate: cancer type (lung), low baseline lymphocyte count, baseline docetaxel exposure
Borg et al. (2004) [33] Prospective Various hematologic and solid tumors Various Univariate: cancer type (hematologic), CSF use a

Multivariate: CD4 lymphocytes ≤450/μL, high risk chemotherapy
Castagnola et al. (2011) [35] Prospective Pediatric CNS Various Univariate: presence of central venous catheter

Multivariate: standard or PBSCT chemotherapy (versus gentle), low granulocyte count at neutropenia onset
Chan et al. (2012) [38] Retrospective Breast AC Univariate: BMI <23 kg/m2, increasing BSA a

Multivariate: BMI <23 kg/m2
Choi et al. (2003) [34] Prospective Lymphoma and various solid tumors Various Univariate: lymphocyte count ≤500/μL or 700/μL at day 3 or day 5

Multivariate: lymphocyte count ≤700/μL at day 5
Cullen et al. (2007) [44] Retrospective Lymphoma and various solid tumors Various Univariate:

FN in cycle 1 and across all cycles: cancer type

FN-related hospitalization in cycle 1: cancer type, poor performance status, non-adjuvant chemotherapy

FN-related hospitalization across all cycles: cancer type, poor performance status, non-adjuvant chemotherapy, age


FN in cycle 1 and across all cycles: cancer type (testis)

FN-related hospitalization in cycle 1 and across all cycles: cancer type (testis and SCLC), poor performance status
Laskey et al. (2012) [15] Retrospective Ovarian Various Univariate: age >60 years

Multivariate: age >60 years, non-carboplatin regimen
Lyman et al. (2003) b [13] Retrospective NHL CHOP Univariate: age ≥65 years, ≥1 comorbidity, cardiovascular disease, renal disease, baseline hemoglobin <12 g/dL, >80% planned average RDI, no prophylactic CSF use

Multivariate: age ≥65 years, cardiovascular disease, renal disease, baseline hemoglobin <12 g/dL, >80% planned average RDI, no prophylactic CSF use
Lyman et al. (2003) c [16] Retrospective NHL Various Univariate: age ≥65 years, female sex, BSA <2.0 m2, any comorbid condition, albumin ≤3.5 g/dL, baseline ANC <1500 mm–3, planned average RDI ≥80%

Multivariate: age ≥65 years, albumin ≤3.5 g/dL, baseline ANC < 1500 mm–3, hepatic comorbidity, planned average RDI ≥80%
Lyman et al. (2011) d [31] Prospective Lymphoma and various solid tumors Various Univariate: prior chemotherapy, cancer type, type of chemotherapy, CSF primary prophylaxis a

Multivariate: prior chemotherapy, alkaline phosphatase >120 u/L, bilirubin >1 mg/dL, GFR, WBC, cancer type, immunosuppressive medication, planned RDI ≥85%, type of chemotherapy, CSF primary prophylaxis a
Moreau et al. (2009) [32] Prospective Various hematologic cancers Various Univariate: underlying disease, high chemotherapy score, first cycle of a new treatment line

Multivariate: underlying disease, very aggressive chemotherapy, stem cell transplantation, bone marrow involvement; BSA ≤2 m2, baseline monocyte count <150/μL, interaction between the first cycle in the same treatment line and baseline hemoglobin levels
Ng et al. (2011) e [26] Retrospective NHL CHOP-based Univariate: advanced disease stage, lactate dehydrogenase >400, positive blood cultures, chemotherapy administered Q21D

Multivariate: positive blood cultures, chemotherapy administered Q21D, renal dysfunction
Ozawa et al. (2008) [20] Prospective Various solid tumors Docetaxel Univariate: poor performance status, low albumin levels, high docetaxel AUC

Multivariate: poor performance status, docetaxel AUC
Ray-Coquard et al. (2003) [19] Retrospective NHL Various Univariate: lymphocytes ≤700/μL at day 1, high risk chemotherapy, female sex, poor performance status, cancer type

Multivariate: lymphocytes ≤700/μL at day 1, high risk chemotherapy
Rivera et al. (2003) [37] Retrospective Breast FAC Univariate: low first cycle ANC nadir

Multivariate: low first cycle ANC nadir
Scott et al. (2003) [24] Retrospective NHL CHOP Univariate: BSA <1.9 m2, female sex, limited-stage disease, <7 days of CSF secondary prophylaxis, CSF primary prophylaxisa

Multivariate: BSA <1.9 m2, CSF primary or secondary prophylaxisa

a Reduced FN risk was observed.

b Risk factors for onset and timing of first FN event were evaluated.

c Risk factors for hospitalization for FN were evaluated.

d Risk factors for cycle 1 severe neutropenia and FN were evaluated.

e Risk factors for breakthrough FN (FN despite pegfilgrastim prophylaxis) were evaluated.

AC, doxorubicin/cyclophosphamide; ANC, absolute neutrophil count; AUC, area under the plasma concentration versus time curve; BMI, body mass index; BSA, body surface area; CSF, colony-stimulating factor; FAC, fluorouracil/doxorubicin/cyclophosphamide; GFR, glomerular filtration rate; PBSCT, peripheral blood stem cell transplant; Q21D, every 21 days; RDI, relative dose intensity; SCLC, small-cell lung cancer; WBC, white blood count.

Table 4 Studies reporting on genetic-related risk factors for FN.

Study citation Study type Malignancy Chemotherapy Factors associated with FN risk
McLeod et al. (2010) [46] Retrospective Colorectal Various GSTP1 T/T genotype, a UGT1A1 -3156 C>T SNP
Okishiro et al. (2012) [47] Retrospective Breast FEC TP53 R72P C/C genotype (versus G/G and G/C), combination of TP53 R72P C/C genotype and MDM2 SNP309 T/T or T/G (versus G/G) genotype
van der Bol et al. (2010) [48] Retrospective Various Irinotecan MBL2 promoter HYA haplotype, MBL2 -550 promoter H/H genotype, high MBL2 promoter phenotype b

a Observed in patients treated with fluorouracil/irinotecan/oxaliplatin.

b Observed in patients with the wild-type exon polymorphism (A/A).

FEC, fluorouracil/epirubicin/cyclophosphamide; GSTP1, glutathione S-transferase pi gene; MDM2, murine double minute 2 gene; MBL2, mannose-binding lectin 2 gene; SNP, single nucleotide polymorphism; TP53, tumor protein 53 gene; UGT1A1, uridine diphosphate glucuronosyltransferase 1A1 gene.

2.1.1. Age

Four studies found older age to be a risk factor for the development of FN [12], [13], [14], and [15]. Three of these studies were in NHL [12], [13], and [14], and one study was in ovarian cancer [15] . Different cut points for age were observed depending on tumor type, with 65 years used for NHL and 60 years used for ovarian cancer.

Furthermore, one study found advanced age to be a risk factor for FN-related hospitalization [16] . In a retrospective analysis of community oncology practices in NHL, the risk of hospitalization for FN was significantly higher in patients ≥65 years old (P < 0.001), which was most evident during the first cycle of chemotherapy [16] . Although older patients may benefit from aggressive chemotherapy, they are usually treated with lower doses in order to minimize the occurrence of FN and its complications. It has been suggested that effective management of the risk for developing FN is important so that older patients can receive optimal chemotherapy dosing [17] and [18].

2.1.2. Performance status

Four studies have shown that poor performance status is a risk factor for the development of FN [12], [19], [20], and [21]. These studies were conducted in patients with various tumor types, including NHL and breast and lung cancer. It has been suggested that physiological age, as denoted by performance status, may serve as a better predictor of risk than chronological age in older patients [22] . Where both age and performance status have been evaluated, both were independent risk factors for FN.

2.1.3. Gender

Three studies, two in NHL and one in small-cell lung cancer, have found that female gender is a risk factor for the development of FN or hospitalization for FN [16], [23], and [24]. Most studies did not evaluate or report significant associations of neutropenic complications with patient gender.

2.1.4. Comorbidities

Four studies in the current review have shown that the presence of comorbid conditions with cancer is a significant risk factor for FN or FN-related hospitalization [13], [16], [25], and [26]. In patients with NHL treated with CHOP-based chemotherapy, renal disease and cardiovascular disease were significantly associated with an increased risk for a first FN event [13] , and the presence of hepatic comorbidity was found to be a risk factor for hospitalization for FN [16] . Furthermore, renal dysfunction was found to be associated with a higher risk for breakthrough FN [26] .

Previous studies have demonstrated that a number of major comorbidities are associated with the risk of mortality in hospitalized patients with FN, and the risk increases in direct proportion to the number of comorbidities [1] and [25]. Likewise, in the current review, the risk for FN was found to increase with the number of comorbidities. Hosmer et al. developed and validated a predictive model for the risk of FN based on SEER-Medicare data from patients with breast, lung, prostate, or colorectal cancer [25] . In this large study of elderly patients, the presence of comorbid conditions was significantly associated with an increased risk for FN. In addition, the risk for FN increased with the number of comorbidities (one comorbid condition, odds ratio [OR] = 1.13, P = 0.02; two comorbid conditions, OR = 1.39, P < 0.001; three comorbid conditions, OR = 1.81, P < 0.001) [25] .

2.1.5. Laboratory abnormalities

Many studies have found that abnormal laboratory values, often indicative of comorbid conditions, disease extent, or the effect of chemotherapy, are important risk factors for FN or FN-related hospitalization [12], [13], [14], [16], [19], [20], [21], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], and [37]. These studies were performed in various tumor types, including NHL, myeloma, and breast, non-small cell lung, colorectal, and prostate cancer. Such laboratory abnormalities include low lymphocyte or neutrophil counts; low serum albumin or hemoglobin; increased lactate dehydrogenase, bilirubin, or alkaline phosphatase; as well as positive blood cultures.

Baseline laboratory abnormalities have been incorporated into FN risk models. A predictive model for FN risk was retrospectively developed in patients with breast cancer treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide [27] , which was later validated in patients treated with adjuvant docetaxel, doxorubicin, and cyclophosphamide [28] . In this risk model, patients with low pretreatment absolute lymphocyte count (≤1.5 × 109 L–1) and low pretreatment ANC (≤3.1 × 109 L–1) were at the highest risk for developing FN. Furthermore, one study prospectively developed and evaluated a risk model for severe neutropenia and FN in patients with various tumor types, including lymphoma and breast, lung, ovarian, and colorectal cancer [31] . In this study, elevated aspartate aminotransferase (>35 μ/L), alkaline phosphatase (>120 μ/L), or bilirubin (>1 mg/dL), or reduced white blood count or estimated glomerular filtration at baseline were associated with severe neutropenia or FN in cycle 1.

Changes in laboratory values after treatment with chemotherapy have also been evaluated as risk factors for FN. One study in elderly patients with breast cancer found that decreases in white blood count, absolute neutrophil count, or hemoglobin from cycle 1 to cycle 2 were significant predictors for FN in subsequent cycles [30] . Another study in breast cancer validated previous findings that the nadir value of the first cycle absolute neutrophil count is predictive of FN in later cycles [37] .

2.1.6. Body Mass Index (BMI) and Body Surface Area (BSA)

Four studies have shown that low BMI or low BSA is a risk factor for FN or FN-related hospitalization [16], [24], [32], and [38]. Different cut points were analyzed among the four studies. Another study evaluated FN risk with every 10 kg increase in body weight in patients with NHL using a multivariate logistic regression model [14] . Higher weight was found to be protective against developing FN in cycle 1 (OR = 0.62; 95% CI, 0.43–0.89; P = 0.01) [14] , which most likely reflected reductions in delivered dose intensity associated with dose capping or the use of idealized body weight in dose calculations [14], [39], and [40]. Of note, recent guidelines from the American Society of Clinical Oncology recommend full weight-based dosing of chemotherapy in obese patients with cancer, particularly in the curative setting [39] .

2.2.1. Chemotherapy regimen

Many studies have found that certain chemotherapy agents and regimens, with some being more myelosuppressive than others, as well as delivered dose intensity are significant predictors of FN or FN-related hospitalization [13], [14], [15], [16], [19], [21], [25], [26], [31], [32], [33], [35], [41], and [42]. Anthracyclines (e.g., doxorubicin), taxanes (e.g., docetaxel), alkylators (e.g., cyclophosphamide), and topoisomerase inhibitors (e.g., etoposide) as well as gemcitabine and vinorelbine are particularly myelosuppressive. Other treatment-related factors associated with a higher risk for FN include history of previous chemotherapy and treatment with three or more chemotherapy agents [14], [31], and [41]. It is difficult, however, to fully understand FN risk with chemotherapies because in many clinical trials, chemotherapies are often administered with growth factors as per institutional guidelines or investigators’ discretion.

2.2.2. Neutropenia prophylaxis

Several controlled clinical trials and meta-analyses have demonstrated a significant reduction in the risk of FN in patients randomized to receive primary prophylaxis with granulocyte colony-stimulating factors following the initiation treatment with chemotherapy [43] . Current clinical guidelines recommend routine primary prophylaxis with colony-stimulating factors (CSFs) when the risk for FN is ≥20% [8], [9], and [10]. The eight studies identified in this review have likewise shown that patients who received CSF prophylaxis had significantly lower risk for FN or FN-related hospitalizations [12], [13], [14], [16], [24], [31], [33], and [41]. The studies were conducted in various tumor types, including NHL, breast, lung, colorectal, and ovarian cancer.

Furthermore, in a breast cancer study by Jenkins et al., patients who received prophylaxis with antibiotics had a significantly lower incidence of FN than those who did not (8% versus 22%; P = 0.001) [28] . This protective effect was most evident in the first three cycles of chemotherapy (5% versus 17%; P = 0.002) [28] .

2.3.1. Tumor type

Seven studies have shown that the type of malignancy is a significant predictor of FN [19], [21], [25], [31], [32], [33], and [44].

2.3.2. Advanced disease

Six studies have found advanced disease (i.e., higher disease stage or bone marrow involvement) to be a significant predictor of FN [12], [24], [25], [26], [32], and [45]. These studies were performed in various cancers, including NHL, breast, ovarian, lung, colorectal, and prostate cancer.

2.3.3. Genetic risk factors

Three studies were identified that evaluated genetic-related risk factors for FN, as summarized in Table 4 . The three studies were retrospective and were conducted in various solid tumors, including breast, colorectal, and lung cancer. In a study in metastatic colorectal cancer, McLeod et al. found that GSTP1 genotype was associated with FN risk in patients treated with fluorouracil + oxaliplatin (FOLFOX); UGT1A1 genotype was also associated with FN risk when data were pooled across the three arms of the study (FOLFOX, fluorouracil + irinotecan, and irinotecan + oxaliplatin) [46] . In a study in breast cancer, Okishiro et al. found that MDM2 SNP309 and TP53 R72P genotypes were significantly associated with developing FN in patients treated with 5-FU+ epirubicin + cyclophosphamide (FEC) [47] . Furthermore, in a study in various tumor types, van der Bol et al. observed that specific polymorphisms in the MBL2 gene were associated with FN risk in patients treated with irinotecan [48] .

In a recently published paper, Vulsteke et al. evaluated 26 single-nucleotide polymorphisms (SNPs) in patients with breast cancer treated with FEC [49] . Specific SNPs in the drug transporter gene ABCC1/MRP1, as well as SNPs in the UGT2B7 and FGFR4 genes, were significantly associated with developing FN [49] .

3. Risk factors for FN in pediatric patients

Most of the studies identified in this report were in adult patients with cancer. One study was identified that evaluated FN risk factors in pediatric patients. This study was a single center prospective study in pediatric patients with central nervous system tumors [35] . In a multivariate analysis, low granulocyte count and type of treatment (standard chemotherapy and peripheral blood stem cell transplant versus gentle chemotherapy) were significantly associated with developing FN [35] .

4. Limitations

Several limitations of the studies summarized in this report should be noted. The heterogeneity in the patient populations, treatment regimens, study designs, and analytical methods make it difficult to compare studies. The definition of FN also differed among studies or was not specified in the published articles. These differences may have contributed to inconsistent findings for risk factors for FN. Many of the studies were also retrospective in nature and were conducted in relatively small populations. Although risk models have been developed, the validation of some of these models in external institutions with independent datasets is lacking. Two FN risk models have been validated using a split-sample methodology, both of which were in mixed tumor populations; further independent validation of these models in other cohorts is important [25] and [31]. In addition, Jenkins et al. performed a partial validation with an independent dataset of an FN risk model in patients with breast cancer, yet limitations with the accuracy of the model were noted, and additional independent validation is needed [28] . To our knowledge, one purely independent validation of FN risk models has been performed thus far. Schwenkglenks et al. externally validated previously published FN risk models using the independent, observational IMPACT NHL database; interestingly, they found a reduction in the performance (sensitivity) of the models [50] . This finding underscores the need to further refine the predictive ability of FN risk models, possibly by the inclusion of genetic factors and/or biomarkers into the model. The clinical validity and clinical utility of risk models for FN have yet to be demonstrated.

5. Conclusions

Various risk factors for FN have been identified, and risk models have been developed. The studies discussed here have identified older age, poor performance status, presence of comorbidities, low baseline white blood cell counts, low BMI/BSA, advanced disease, and the use of myelosuppressive chemotherapy agents as significant predictors for the development of FN or hospitalization for FN. Furthermore, studies reporting on genetic analyses identified certain molecular markers, such as specific SNPs, to be risk factors for FN. However, as new agents and regimens enter clinical practice, these risk factors for FN may change with time. The National Comprehensive Cancer Network®, American Society of Clinical Oncology, and the European Organization for Research and Treatment of Cancer recommend prophylactic use of CSFs in patients with ≥20% risk of developing FN, as stated in their current guidelines [8], [9], and [10]. However, prophylactic CSF is not recommended for patients at low risk, and alternative treatment options are appropriate. With a clearer understanding of the risk factors for FN, physicians may better identify high risk patients and treat them accordingly.

Conflict of interest statement

Gary H. Lyman receives research funding from Amgen Inc. Ruth Pettengell received honoraria from Amgen Inc. and Roche. Esteban Abella was an employee of and owns stock in Amgen Inc.


Didier Kamioner, Oncology/Hematology, Hôpital Privé de l’Ouest Parisien, Rue Castiglione del Lago, F-78190 Trappes, France.


We thank Benjamin Scott, PhD, of Complete Healthcare Communications, Inc. for his assistance with performing the literature search and Jenilyn Virrey, PhD, of Amgen Inc. for her assistance with writing this article. This study was funded by Amgen Inc. The study sponsor and authors were involved in the study design; collection, analysis, and interpretation of data; writing of the manuscript; and decision to submit the manuscript for publication.


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Gary H. Lyman MD, MPH, FASCO, FRCP(Edin), is Codirector of the Hutchinson Institute for Cancer Outcomes Research and a Member of the Division of Public Health Sciences, at the Fred Hutchinson Cancer Research Center. He was previously professor of Medicine and Director of Comparative Effectiveness and Outcomes Research-Oncology at Duke University and the Duke Cancer Institute. He is also a senior fellow at the Duke Center for Clinical Health Policy Research. He received his undergraduate and medical degree from the State University of New York in Buffalo and completed internal medicine residency at the University of North Carolina in Chapel Hill. He subsequently completed a Clinical Hematology/Oncology Fellowship at the Roswell Park Memorial Institute and a Postdoctoral Fellowship in Biostatistics at the Harvard School of Public Health and the Dana Farber Cancer Center. He is active with the American Society of Clinical Oncology (ASCO) serving on the ASCO Board of Directors, co-Chair of the Breast Cancer and Survivorship Guideline Advisory Groups as well as chairing the Guideline Methodology Committee and several individual guidelines including those related to Prevention and Treatment of Venous Thromboembolism in Cancer, Sentinel Node Biopsy in Early-Stage Breast Cancer and Melanoma, Use of Antiemetics in Patients Receiving Cancer Chemotherapy and Appropriate Chemotherapy Dosing in Obese Patients with Cancer. He is also a member of the ASCO Biomarkers Guideline Working Group, the Comparative Effectiveness Research Task Force, and the Cost of Care Task Force, and in 2010 he received the prestigious ASCO Statesman Award. He is an advisor to the US Food and Drug Administration and the Oncology Drug Advisory Committee. He is Editor-In-Chief of Cancer Investigation and on the Editorial Board of the Journal of Clinical Oncology and several other specialty journals. In addition to serving as a Fellow of ASCO, he is a Fellow of the Royal College of Physicians (Edinburgh), the American College of Physicians, the American College of Preventive Medicine, and the American College of Clinical Pharmacology. His research interests include personalized cancer supportive care, comparative effectiveness and outcomes research related to targeted therapies and biomarkers, mathematical and statistical prognostic and predictive models, advanced methods of evidence synthesis in support of clinical practice guidelines and population studies of patterns of cancer treatment, and the impact of health disparities on the quality of cancer care. He has authored or edited more than 10 books and more than 400 articles in the scientific literature.


Esteban Abella, MD, joined Amgen Inc. in January 2010 as a Clinical Research Medical Director providing support to the Neupogen®/Neulasta® team. He subsequently became the North American Medical Lead until his transition to the Global Development Lead. During his tenure at Amgen Inc., he has made numerous contributions to the team, which included oversight of the collaboration with the Awareness of Neutropenia in Chemotherapy Study Group. Steve studied Ancient History and Biology at the University of Pennsylvania and received his medical degree from Universidad Central del Este, San Pedro de Macoris, Republica Dominica. He completed his training in Pediatrics, including a Pediatric Hematology/Oncology Fellowship at The Children's Hospital of Michigan, Wayne State University School of Medicine in Detroit. Steve was a faculty member at Wayne State University School of Medicine and the Barbara Ann Karmanos Cancer Institute. He has been the recipient of numerous honors and awards, and he has published extensively in the fields of bone marrow transplantation and clinical research.


Ruth Pettengell, MD, PhD, is a Reader in Clinical Sciences at St George's, University of London. She has a particular interest in lymphoma and hematological toxicities. Her medical career started in New Zealand, where she specialized in Medical Oncology before moving to the UK where she obtained her PhD on the ‘Characterization and Clinical Uses of Blood Progenitor Cells’ from the University of Manchester, UK, where she developed protocols for high dose therapy and stem cell transplantation. Following this, she took a Senior Clinical Research position at the Department of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York, USA, studying the interactions between hemopoietic progenitor cells and bone marrow stroma. She is a member of the European Organization for Research and Treatment of Cancer working party that formulated European guidelines for the use of granulocyte colony-stimulating factors to reduce the incidence of chemotherapy-induced febrile neutropenia in adult oncology patients. She chairs the Impact of Neutropenia in Chemotherapy European study group developing models for febrile neutropenia risk assessment and has more than 150 publications, review articles, book chapters, and editorials in the field of hematology and oncology.


a Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA, USA

b Amgen Inc., Thousand Oaks, CA, USA

c St. George's University of London, London, UK

lowast Corresponding author at: Fred Hutchinson Cancer Research Center, P.O. Box 19024, M3-B232; Seattle WA 98109-1024, USA.

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