chemotherapy-induced neutropenia : risks, consequences, and new directions for its management

Chemotherapy-Induced NeutropeniaRisks, Consequences, and New Directions for Its Management

Jeffrey Crawford, M.D.1

David C. Dale, M.D.2

Gary H. Lyman, M.D., M.P.H.3

1 Divisions of Oncology and Hematology, Duke Uni-versity Medical Center, Durham, North Carolina.

2 Department of Medicine, University of Washing-ton, Seattle, Washington.

3 James P. Wilmont Cancer Center, University ofRochester Medical Center, Rochester, New York.

Supported by an unrestricted educational grantfrom Amgen Inc.

Dr. Crawford and Dr. Dale receive research sup-port from and are consultants for Amgen Inc. andalso are members of its Speakers’ Bureau.

Dr. Lyman receives grant support from Amgen Inc.and is a member of its Speakers’ Bureau.

Address for reprints: Jeffrey Crawford, M.D., Divi-sions of Oncology and Hematology, Duke Univer-sity Medical Center, P.O. Box 25178 Morris Build-ing, Durham, NC 27710-0001; Fax: (919) 681-5864; E-mail: [email protected]

Received April 23, 2003; revision received October1, 2003; accepted October 2, 2003.

Cytotoxic chemotherapy suppresses the hematopoietic system, impairing host

protective mechanisms and limiting the doses of chemotherapy that can be toler-

ated. Neutropenia, the most serious hematologic toxicity, is associated with the risk

of life-threatening infections as well as chemotherapy dose reductions and delays

that may compromise treatment outcomes. The authors reviewed the recent liter-

ature to provide an update on research in chemotherapy-induced neutropenia and

its complications and impact, and they discuss the implications of this work for

improving the management of patients with cancer who are treated with myelo-

suppressive chemotherapy. Despite its importance as the primary dose-limiting

toxicity of chemotherapy, much concerning neutropenia and its consequences and

impact remains unknown. Recent surveys indicate that neutropenia remains a

prevalent problem associated with substantial morbidity, mortality, and costs.

Much research has sought to identify risk factors that may predispose patients to

neutropenic complications, including febrile neutropenia, in an effort to predict

better which patients are at risk and to use preventive strategies, such as prophy-

lactic colony-stimulating factors, more cost-effectively. Neutropenic complications

associated with myelosuppressive chemotherapy are a significant cause of mor-

bidity and mortality, possibly compromised treatment outcomes, and excess

healthcare costs. Research in quantifying the risk of neutropenic complications

may make it possible in the near future to target patients at greater risk with

appropriate preventive strategies, thereby maximizing the benefits and minimizing

the costs. Cancer 2004;100:228 –37. © 2003 American Cancer Society.

KEYWORDS: chemotherapy, myelosuppression, neutropenia, febrile neutropenia,infection, risk factors, colony-stimulating factors.

Cytotoxic chemotherapy predictably suppresses the hematopoieticsystem, impairing host protective mechanisms. Neutropenia is

the most serious hematologic toxicity of cancer chemotherapy, oftenlimiting the doses of chemotherapy that can be tolerated. The degreeand duration of the neutropenia determine the risk of infection (Fig.1).1,2 The Common Toxicity Criteria of the National Cancer Institute isthe most commonly used scale for grading the severity of the cyto-penias associated with cancer chemotherapy; it delineates neutrope-nia into 4 grades (Table 1).3

Chemotherapy predisposes patients with cancer to infectionsboth by suppressing the production of neutrophils and by cytotoxiceffects on the cells that line the alimentary tract. Neutrophils are thefirst line of defense against infection as the first cellular component ofthe inflammatory response and a key component of innate immunity.Neutropenia blunts the inflammatory response to nascent infections,allowing bacterial multiplication and invasion. Because neutropeniareduces the signs and symptoms of infection, patients with neutro-

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© 2003 American Cancer SocietyDOI 10.1002/cncr.11882

penia often may present with fever as the only sign ofinfection. In this setting, patients with fever and neu-tropenia, or febrile neutropenia (FN), must be treatedaggressively, typically with intravenous antibiotics andhospitalization, because of the risk of death from rap-idly spreading infection.

The availability of hematopoietic growth factorsand improvements in antibiotic therapy have changedgreatly how clinicians approach the management ofneutropenia, yet this complication remains a centralconcern in the delivery of cancer chemotherapy. Thisreview summarizes the clinical consequences of che-motherapy-induced neutropenia (CIN) and describescurrent efforts to predict which patients are likely toexperience neutropenic complications— delays andreductions in chemotherapy doses, FN, bacterial andfungal infections, and septic deaths.

Epidemiology of CIN and Risk of NeutropenicComplicationsAll patients who are treated with chemotherapy are atrisk for the development of neutropenic complica-tions, but it is difficult for clinicians to predict whichpatients or populations of patients clearly are atgreater risk. Identified risk factors for neutropenia canbe classified as patient-specific or regimen-specific.

Patient-specific risk factorsBecause chemotherapy regimens are standardized bycancer type, patient-specific risk factors are particu-larly important in any given treatment setting. Patient-specific risk factors are type of cancer and diseasestage, measures of pretreatment health, comorbidconditions, performance status, and age. With respectto disease type, it is clear that patients with hemato-logic malignancies are at greater risk for neutropeniathan patients with solid tumors because of the under-lying disease process as well as the intensity of thetreatment that is required.

In a review of 18 published risk models that weredeveloped to assess neutropenic risk, Lyman et al.described 2 types of models—those that predict severeneutropenia or FN or reduced dose intensity (Type 1)and those that predict bacteremia or other conse-quences of FN (Type 2).4 The risk factors that werevalidated in at least 2 models of either type were age,performance status, dose intensity, and serum lactatedehydrogenase (LDH) level for Type 1 models and age,leukemia or lymphoma, high temperature, and lowblood pressure on admission for Type 2 models. Au-thors of another review found many of the same riskfactors, including age and performance status.5

Laboratory abnormalities that indicate either co-morbid conditions or disease extent may predict neu-tropenic complications. For example, retrospectivestudies have found predictive value in pretreatmentleukocyte counts.6 In 1 prospective study of patientswith aggressive non-Hodgkin lymphoma (NHL) whowere treated with cyclophosphamide, doxorubicin,vincristine, and prednisone (CHOP), it also was foundthat a serum albumin concentration � 3.5 g/dL, anLDH level greater than normal, and bone marrowinvolvement of the lymphoma all were significant pre-dictors of life-threatening neutropenia (absolute neu-trophil count [ANC] � 0.5 � 109/L) or FN (ANC � 0.5� 109/L and body temperature � 38.3 °C).7

The role of age in the susceptibility to neutropeniccomplications has been explored extensively. Initialattempts to document older age (� 65 years or � 70years) as a risk factor were confounded by the exclu-sion of elderly patients from clinical trials as well asinclusion criteria that admitted only the most other-wise healthy elderly patients in those trials in whicholder age was not itself an exclusion criterion.8 Incontrast, 7 of the 9 studies examined in a review of riskfactors for severe neutropenia or FN demonstrated asignificant effect of age on risk.5 This included a ret-rospective practice pattern study, which showed thatolder patients with NHL had more hospitalizations forFN and were given a lower relative dose intensity of

FIGURE 1. Incidence of serious infection, by nadir absolute neutrophil count

(ANC) and duration of neutropenia. Adapted from Bodey GP, Buckley M, Sathe

YS, Freireich EJ. Quantitative relationships between circulating leukocytes and

infection in patients with acute leukemia. Ann Intern Med. 1966;64:328–340.

TABLE 1Grades of Neutropeniaa

Grade Absolute neutrophil count (� 109/L)

0 Within normal limits1 � 1.5 to � 2.02 � 1.0 to � 1.53 � 0.5 to � 1.04 � 0.5

a According to the National Cancer Institute Common Toxicity Criteria, version 2.0.3

Chemotherapy-Induced Neutropenia/Crawford et al. 229

chemotherapy.9,10 In addition, a prospective study inwomen who were treated with doxorubicin and cyclo-phosphamide (AC) as adjuvant chemotherapy forbreast carcinoma showed that, in women age � 70years, there was a greater incidence, duration, andseverity of neutropenia and also a trend toward deeperANC nadirs with greater age.11 Furthermore, studies ofrisk factors for the toxicity of chemotherapy in olderpatients are underway. In a pilot trial in patients age� 70 years who were treated with chemotherapy forsolid tumors or nonleukemic hematologic malignan-cies, pretreatment parameters (such as increased dia-stolic blood pressure, bone marrow invasion, andabove-normal LDH levels) were associated withgreater toxicity.12

Age itself is a general risk factor for the develop-ment of severe neutropenia or FN, and it also may beassociated with other patient characteristics that af-fect that risk. In some studies, it has been found thatpoor performance status (e.g., World Health Organi-zation Grade � 1), as a measure of frailty, is a signif-icant risk factor.5 Thus, a patient’s physiologic age,rather than chronologic age, may be a more accuratepredictor of the neutropenic risk. One approach todetermining a patient’s physiologic age is to use acomprehensive geriatric assessment, but this has notbeen adopted widely in oncology practice.13 Con-versely, dose reductions in chemotherapy due to therisk of myelosuppression in older patients that arebased on age alone are not appropriate, because oth-erwise healthy older patients may obtain equal benefitfrom chemotherapy if they are treated as aggressivelyas younger patients.8 The National ComprehensiveCancer Network, instead, recommends giving patientsage � 70 years prophylactic hematopoietic growthfactors to improve the therapeutic index of myelosup-pressive chemotherapy, such as CHOP, in this popu-lation (Table 2).14 In addition, the clinical evidencesupports recognizing the elderly as one of the specialpopulations for which the guidelines of the AmericanSociety of Clinical Oncology (ASCO) suggest consider-

ing primary prophylaxis with growth factors in con-junction with myelosuppressive chemotherapy.15,16

Another patient-specific risk factor for later neu-tropenic complications is the patient’s early hemato-logic response to chemotherapy.5 This has the advan-tage of being a functional assessment of the effect oftreatment on the patient’s bone marrow. The firstcycles of treatment can show which patients are atrisk, after which dose modifications or prophylacticgrowth factors are often used, thus reducing the risk inlater cycles. Studies have shown the predictive value ofthe first-cycle nadir in leukocyte counts17,18 and de-creases in hemoglobin levels18 for predicting neutro-penic complications in later cycles. This conditionalapproach to determining which patients are at greaterrisk may be useful with regimens with which the riskin the early cycles is low. With many regimens, how-ever, most of the neutropenic complications may oc-cur in the early cycles (see below). For this reason,unconditional strategies based on pretreatment riskfactors would be preferable for determining whichpatients are at greater risk, because they would lead tothe use of supportive measures before most compli-cations would occur, not after they had occurred.

The use of growth factors early in chemotherapyalso affects the risk of neutropenic complications bothin the initial cycle and in subsequent cycles of therapy.Grade 4 neutropenia occurred during the first cycle in� 80% of patients with advanced breast carcinomawho were treated with docetaxel and doxorubicin in 2clinical trials and declined to � 40% by Cycle 4.19,20

Those patients were given either pegfilgrastim or dailyinjections of filgrastim, and it appears that the earlyadministration of these growth factors affected the riskof neutropenia in later cycles, perhaps due to a prim-ing effect on myeloid precursors.21 This pattern ofreduced severity of neutropenia in the later cycles alsowas seen in pivotal trials of filgrastim in the U.S. andEurope, in which the duration of Grade 4 neutropeniawas reduced from 3 days in Cycle 1 to 1 day in the latercycles.22,23 In contrast, in the placebo arms of theserandomized studies in patients with lung carcinoma,the duration of Grade 4 neutropenia was 6 days acrossall cycles.

Regimen-specific risk factorsThe chemotherapy regimen is one of the primary de-terminants of the risk of neutropenia, and some regi-mens are more myelotoxic than others. For example,combined cyclophosphamide, methotrexate, and5-fluorouracil is less toxic than AC or combined cyclo-phosphamide, doxorubicin, and 5-fluorouracil and,consequently, often is preferred in elderly patientswith breast carcinoma.24 To determine more accu-

TABLE 2National Comprehensive Cancer Network Guidelines to MinimizeToxicity of Chemotherapy in Elderly Patients (> 70 Years)a

Use hematopoietic growth factors in patients treated with combinationchemotherapy with dose intensity equivalent to that of CHOP

Maintain hemoglobin level � 120 g/L with erythropoietinConsider adjusting doses of renally excreted drugs according to patient’s

glomerular filtration rate

CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone.a See Balducci and Yates.14

230 CANCER January 15, 2004 / Volume 100 / Number 2

rately the risks associated with commonly used che-motherapy regimens, we recently surveyed the litera-ture for the rates of neutropenia that were reported inrandomized clinical trials of chemotherapy.25 We lim-ited our survey to trials in patients with early-stagebreast carcinoma and NHL, because these malignan-cies can be treated with curative intent with appropri-ate doses of chemotherapy. We found that the rates ofmyelosuppression and associated complications werereported infrequently. Furthermore, when reported,the rates for the same and similar regimens variedgreatly, making it difficult to determine the actualrisk.25 In the absence of clearly defined, regimen-spe-cific risks, assessing the patient-specific risk factors ineach patient may have greater value in determining inwhich patients supportive intervention would be ap-propriate.

The risk of neutropenia also has been related tothe phase of therapy, with the perhaps counterintui-tive, but well supported, conclusion that the greatestrisk is in the earliest cycles. In 1 study in older patientswith aggressive NHL who were treated with CHOP,63% of the toxic deaths (mostly neutropenia-related)occurred in the first cycle of the 6-cycle to 8-cycleregimens (Fig. 2).26 A recent practice pattern studyalso showed that 65% of the hospitalizations for FNoccurred in the first 2 cycles of chemotherapy forintermediate-grade NHL.27 In addition, in patientswith advanced breast carcinoma who were treatedwith docetaxel and doxorubicin in 2 clinical trials,approximately 75% of the episodes of FN during thecourse of chemotherapy occurred in the first cycle.28

Again, with a secondary prophylaxis strategy of wait-

ing until a neutropenic complication occurs to imple-ment supportive measures, most of the complicationsthese measures are intended to prevent already mayhave occurred.

Consequences of FNThe relation between the neutrophil count and therisk of infection has been known for more than 30years.1 In addition, for nearly as long, it has beenknown that the prompt administration of empiric an-tibiotics, before laboratory confirmation of infection,is crucial in patients with FN, because infection canprogress rapidly in these patients.29 Indeed, there is a50% likelihood of an established or occult infection inpatients with FN, and 20% of febrile patients withsevere neutropenia (ANC � 0.5 � 109/L) are bactere-mic,30 but the initial phase of infection often is notapparent clinically because of the lack of an inflam-matory response. The sites of infection most often arein the alimentary tract, the lungs, and the skin, whereinvasive procedures provide entry for pathogens.30,31

The most common organisms that infect patients withcancer and neutropenia in general, as well as the mostcommon causes of bacteremia, are gram-negativerods, such as Escherichia coli, Klebsiella pneumoniae,and Pseudomonas aeruginosa, and aerobic, gram-pos-itive cocci, such as Staphylococcus and Streptococcusspecies and Enterococcus.30,31 There has been a shift inthe most common infectious agents since the wide-spread use of effective empiric antibiotics, from highlylethal, gram-negative bacilli to more indolent, gram-positive bacterial and fungal pathogens.32

The Infectious Diseases Society of America (IDSA)has published guidelines for the treatment of neutro-penic patients with cancer who become febrile.31 Forthe majority of patients with FN, hospitalization withintravenous antibiotics remains the standard of care.Some low-risk patients may be managed with oralantibiotics on an outpatient basis,33–36 but strict ad-herence to a standard of care and close follow-up areneeded in this population. The antibiotics must bechosen carefully, taking into consideration the insti-tution’s patterns of infection and antibiotic suscepti-bility as well as patient-specific factors, such as drugallergies, and the potential for toxicities, such as renaltoxicity from drug interactions or excessive serum lev-els of the drugs. Moreover, hospitalized patients areexposed to additional pathogens and are at risk fornosocomial infections. Hospitalization with FN con-tinues to be associated with significant mortality (8%of more than 40,000 nontransplantation adult patientswith cancer in a recent analysis of 1995–2000 dis-charge data from the University HealthSystems Con-sortium37) as well as possible detrimental effects on

FIGURE 2. Treatment-related deaths, by chemotherapy cycle, in patients

with aggressive non-Hodgkin leukemia who were treated with cyclophospha-

mide, doxorubicin, vincristine, and prednisone. There were 35 deaths in 267

consecutive patients (13%), including 22 deaths (63%) that occurred in the first

cycle, and 29 of the 35 deaths (83%) were infection-related. Adapted from

Gomez H, Hidalgo M, Casanova L, et al. Risk factors for treatment-related death

in elderly patients with aggressive non-Hodgkin’s lymphoma: results of a

multivariate analysis. J Clin Oncol. 1998;16:2065–2069.


patients’ clinical outcomes because of the discontin-uation of chemotherapy or substantial delays or re-ductions in its delivery. Indeed, a recent analysis thatlinked data from the Surveillance, Epidemiology, andEnd Result Program of the National Cancer Institute todata from a practice pattern survey in patients withaggressive NHL found a significant association be-tween the occurrence of FN, reduction in the numberof cycles of CHOP delivered, and lower 5-year overallsurvival.38

In addition to its clinical impact, FN has economicconsequences that are related to hospitalization andtime lost from work. Indeed, 2 recent economic anal-yses have reported mean lengths of stay in hospital-izations for FN of approximately 10 days, with meantotal costs of � $20,000.37,39 In addition, a study thatexamined the indirect, nonhospital costs of hospital-izations for FN estimated these at approximately$5000 per hospitalization, with the majority of thisamount accounted for by lost wages.40 Finally, FNdirectly affects patients’ quality of life. The hospitalenvironment, separation from family members; thefear of infection, failure of cancer therapy, and death;and invasive procedures in the hospital all contributeto a substantial reduction in the well being of pa-tients.41

Consequences of Afebrile NeutropeniaThe presence of Grade 4 neutropenia after chemother-apy and the absence of fever or other signs of infectionshould alert the clinician to the patient’s risk for de-veloping fever and infection. It is recognized widelythat profound neutropenia (ANC � 0.1 � 109/L) placesa patient at very high risk for serious infectious com-plications. Prophylactic antibiotics may be prescribedin this setting, but the frequency of this practice is notknown. Some oncologists maintain that such use ofprophylactic antibiotics is warranted by the seriousrisk of infection, but infectious disease specialists gen-erally warn against the use of empiric antibiotics, fear-ing the promotion of antibiotic-resistant bacterial andfungal strains. The 2002 guidelines of the IDSA for theprophylactic use of antimicrobial agents in afebrileneutropenic patients state that concern about theproblem of emerging drug-resistant bacteria and fungidue to extensive antibiotic use, plus the fact that suchprophylaxis has not been shown to consistently re-duce mortality rates, leads to the recommendation ofavoiding routine prophylaxis with these drugs in neu-tropenic patients, with the exception of use of tri-methoprim-sulfamethoxazole for patients at risk forPneumocystis carinii pneumonitis.31

Another response to neutropenia is the therapeu-tic use of colony-stimulating factor (CSF), i.e., as treat-

ment after the patient has become neutropenic. Theextent of this practice was shown in a retrospectivesurvey of community oncology practice patterns6 thatfound a wide range in the number of days after che-motherapy that the use of CSF was initiated. In morethan two-thirds of patients who were treated with CSF(27% of all patients), the therapy was initiated 5 ormore days after the chemotherapy, and it was startedin 32% of patients on Days 10 –14, the expected time ofthe ANC nadir.6 CSF treatment for afebrile neutrope-nia clearly is not as effective in preventing neutropeniccomplications as CSF prophylaxis before neutropeniadevelops. In a randomized, controlled trial, Hartmanand colleagues found that treating established neutro-penia with CSF failed to provide the benefits achievedwith prophylactic CSF.42

Chemotherapy dose modifications— delays of thenext cycle and/or dose reductions—are another com-mon consequence of neutropenia and are imple-mented due to a slow recovery of the bone marrowafter a previous course of chemotherapy. Recent prac-tice pattern studies have shown the extent to whichcommunity oncologists delay and reduce the doses ofthe chemotherapy. In 1 study, there were neutrope-nia-related dose modifications in 28% of patients withearly-stage breast cancer (more than once in 61% ofthese patients), and � 85% of the reference chemo-therapy dose intensity was delivered in 30% of pa-tients.43 In another, even larger survey of practice pat-terns in more than 20,000 patients, also in the settingof adjuvant chemotherapy for breast carcinoma, theaverage relative dose intensity was � 85% in morethan half (58%) of patients.44 Dose delays and reduc-tions were even more likely in elderly patients (age� 65 years), with two-thirds (67%) of those patientsreceiving an average relative dose intensity of� 85%.44

Dose delays and reductions also may be instigatedautomatically in certain settings, such as in elderlypatients, because of concerns about a greater risk oftoxicity. In light of the well documented lower survivalin some patients who are treated with less than the fulldoses of the chemotherapy,45– 49 other options shouldbe considered before reducing dose intensity. The re-cently reported results of a large randomized trialdemonstrating improved survival with dose-dense(14-day) adjuvant regimens versus the standard 21-day regimens in patients with early-stage breast car-cinoma provide further support for the hypothesisthat delivered dose intensity is an important determi-nant of outcome.50 Finally, it is interesting to note thata higher incidence of myelosuppression, possibly cor-related with greater dose intensity, was associatedwith greater survival in patients with early-stage breast


carcinoma who were treated with adjuvant chemo-therapy (Fig. 3).51

The extent to which the doses of chemotherapywere modified in major randomized clinical trials alsowas explored in the aforementioned analysis of theliterature on chemotherapy in patients with early-stage breast carcinoma and NHL.52 Data on the re-ceived dose intensity were reported in various ways,and approximately 40% of the studies did not reportcomplete information concerning the delivered doseintensity.52 The majority of the studies described theprotocols by which the doses could be modified, pri-marily in response to hematologic toxicity, but a sig-nificant portion of those studies did not report whatthe actual delivered dose intensity was as a result ofthese dose modifications. The true myelotoxic poten-tial of a regimen cannot be determined from a reportwithout data on both the incidence of neutropeniccomplications and the delivered dose intensity thatwas associated with those complications.

Diminished quality of life is another possible con-sequence of afebrile neutropenia, and it is being ex-plored in current research. Recent inquiries into theimpact of neutropenia on the quality of life of patientswith cancer have found that neutropenia affects pa-tients before infection becomes apparent. In the de-velopment and validation of a neutropenia-specificquality-of-life instrument, 2 subscales became appar-ent, fatigue (distinct from that associated with ane-mia) and worry, which indicates that neutropenia af-fects specific domains of clinical and emotional wellbeing.53 Furthermore, data from a large community

setting showed a significant association between thedepth of the ANC nadir and the decline in quality-of-life measures.54,55 In addition, there are numerousanecdotal reports that patients simply do not feel aswell when their ANC is low. To our knowledge to date,there are no conclusive data showing that neutropeniaimpairs the quality of life of patients with cancer;however, additional studies in this area are needed.Quality of life has become a larger issue in oncologypractice as cancer therapy evolves toward the man-agement of chronic disease and as patient advocacygroups have begun to emphasize decision-making ap-proaches that consider more than just well establishedclinical and economic outcomes.41

In addition to the direct effects of neutropenia onthe risk of infection and quality of life, there is evi-dence that neutropenia is associated with exacerba-tions of other adverse effects of chemotherapy. A ret-rospective analysis of data from a study in patientswith advanced breast carcinoma found that the inci-dence and the timing of nonneutropenic adverseevents (e.g., abdominal pain, anorexia, fatigue, andemesis) were associated significantly with the inci-dence and timing of FN primarily occurring duringDays 5–10 of the chemotherapy cycle.56 Whether theoccurrence of neutropenia predicts the occurrence ofother adverse events or whether neutropenia itself hasa causal role in these events is not clear. However, inthe current study, the greater incidence, severity, andduration of these common adverse events in patientswith FN were independent of factors that increasedthe risk of FN.

The True Cost of NeutropeniaSignificant costs are incurred when FN develops in apatient treated with chemotherapy, as mentionedabove. These costs include both direct medical costsand indirect costs that are borne by the patient and hisor her family. Economic analyses have estimated thedifferent types of aggregate costs that are incurred inhospitalization for FN, and these can be weighedagainst the costs of the use of prophylactic CSFs. Anearly cost-minimization analysis calculated that, whenthe risk of FN was about 40%, the cost of universalprophylactic granulocyte-CSF was equaled by the re-duction in the costs of hospitalization for FN.57 Thisthreshold remains within the 2000 ASCO guidelinesfor the use of CSFs.15 More recent economic analysessuggest that this threshold value should be reevalu-ated. In 1 such economic analysis, the daily institu-tional costs in 1105 patients with cancer treated withchemotherapy who were admitted in 1994 and 1995 tothe H. Lee Moffitt Cancer Center with FN were esti-mated.58 The patients were classified into a group who

FIGURE 3. Actuarial survival in patients with breast carcinoma who were

treated with cyclophosphamide, methotrexate, and 5-fluorouracil, by the pres-

ence or absence of Grade 3 or 4 myelosuppression. Adapted from Mayers C,

Panzarella T, Tannock IF. Analysis of the prognostic effects of inclusion in a

clinical trial and of myelosuppression on survival after adjuvant chemotherapy

for breast carcinoma. Cancer. 2001;91:2246–2257.


had a primary diagnosis of FN and hospital stays thataveraged 8 days and a group that had either a primaryor a secondary diagnosis of FN with other comorbidi-ties and hospital stays that averaged 16 days. Theaverage daily costs were similar in the 2 groups ($1675and $1892), although the resulting total cost wasgreater for the second group with longer stays. Thesecost findings have been confirmed in another recentanalysis of data from the 1995–2000 discharge sum-maries of the 115-member University HealthSystemsConsortium on more than 55,000 hospitalizations forFN.37 With these updated and more inclusive data oncosts, the threshold at which the use of prophylacticCSF becomes cost-neutral is a 23% risk for FN (Fig.4).58,59 Moreover, the use of a treatment model with anoutpatient option for low-risk patients had little effecton the cost-minimization threshold risk, because low-risk patients already have a minor impact on costs,which are dominated by the higher risk patients withcomorbidities and long hospital stays.60

Another economic analysis of adjuvant chemo-therapy for patients with early-stage breast carcinomaused a conditional risk model based on the first-cycleANC nadir and drop in hemoglobin level to determinewhether prophylactic CSF would be used in the sub-sequent cycles.18 If CSFs were used in the 50% ofpatients with the highest risk of FN, then the esti-mated cost per life-year saved was about $34,000 for apatient age 55 years. This estimate is based on as-sumptions about the effect of receiving full-dose che-motherapy on overall survival, and it declines assmaller percentages of the highest risk patients aregiven CSF. The cost per life-year saved with the 50%

cut-off value is within the range of costs for othercommon medical conditions (Fig. 5).59,61

The aforementioned cost estimates include bothdirect (e.g., pharmacy) and indirect (e.g., nursing)medical costs but not nonmedical costs that patientsincur, such as time lost from work and transportationcosts. These costs have been estimated in women withgynecologic malignancies,40 and other surveys areplanned or are underway. A true accounting of theseout-of-pocket costs, in addition to updates of themedical costs, would help in determining when to useprophylactic CSF by adding a societal perspective tothe debate. Focusing on only part of the costs, such asthe direct medical expenses, may lead to cost shiftingand fails to consider the actual financial impact on allaffected parties.

Models for Predicting Risks in Individual PatientsIt has been shown that prophylactic CSF reduces theduration of severe neutropenia and, thus, the risk ofFN,19,20 –23,62 but its use in all patients is not consid-ered cost-effective. Ideally, these drugs would be tar-geted to patients who are at greater risk of neutropeniccomplications and, thus, would be more likely to ben-efit from them. A risk-prediction model would includean inventory of patient characteristics that have beenassociated with the risk of neutropenic complicationsin a given disease and treatment setting. Several stud-ies have found a variety of risk factors in many clinicalsettings, as described above. Compiling these factorsinto a comprehensive risk model would make it pos-sible for clinicians to estimate better the likelihood ofneutropenic complications in individual patients and,thus, use appropriate prophylactic measures.

Risk models, as discussed above, can be based onunconditional factors, such as pretreatment measures,or on conditional factors, such as the patient’s hema-tologic response in the first cycle of chemotherapy.Oncologists often informally use the conditionalmodel, in which CSF is used to treat patients who havehad an episode of FN. Unfortunately, this can result insubjecting many patients to complications that couldhave been prevented. Unconditional models have theadvantage of identifying those patients who are likelyto have neutropenic complications before they areexposed to chemotherapy and its myelosuppressiveeffects.

With many predictors of neutropenic complica-tions now identified, the task remains to test theirvalidity and practicality for clinical use. An ideal riskmodel could be constructed from a prospective regis-try of patients treated with chemotherapy in commu-nity and academic settings, in which data on a varietyof clinical measures could be collected along with

FIGURE 4. Cost-minimization analysis of prophylactic colony-stimulating

factor (CSF) initiated during the first cycle of chemotherapy. The greater direct

costs of hospitalization for febrile neutropenia (FN) (from approximately $1000

per day in 1991 to approximately $1750 per day in 1996) lowered the risk

threshold for cost-effective use of prophylactic CSF from the 40% in the current

American Society of Clinical Oncology guidelines15 to approximately 23%.

Adapted from Lyman GH. A predictive model for neutropenia associated with

cancer chemotherapy. Pharmacotherapy. 2000;20(7 pt 2):104S–111S.


pretreatment and midcycle ANC values. A prospectiveregistry for this purpose was established in 2001, andits initial findings are expected to be available in2004.52,63

ConclusionsDespite the fact that neutropenia is the major dose-limiting toxicity of cancer chemotherapy, the epide-miology of CIN and its clinical and economic conse-quences only recently have begun to be elucidated.With additional research into factors that reliably pre-dict neutropenic complications, researchers may beable to develop a predictive model that clinicians canincorporate easily into their everyday practice. Thegoal of these efforts is to accurately assess a patient’srisk for the development of neutropenic complicationsduring the course of chemotherapy, so that appropri-ate prophylactic measures can be implemented beforethe first cycle of treatment in those patients who are athighest risk and so that such measures can be avoidedin patients at lowest risk. This goal likely will beachieved in the near future, ushering in a new era inthe cost-effective use of hematopoietic growth factors.

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FIGURE 5. Estimated cost per life-year

saved of prophylactic cyclophosphamide,

methotrexate, and 5-fluoruracil (given to

50% of the patients at highest risk of

developing febrile neutropenia) and of

other common medical interventions.

CMF: cyclophosphamide, methotrexate,

and 5-fluorouracil; CSF: colony-stimulat-

ing factor. Adapted from Lyman GH. A

predictive model for neutropenia associ-

ated with cancer chemotherapy. Pharma-

cotherapy. 2000;20(7 pt 2):104S–111S.


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chemotherapy-induced neutropenia : risks, consequences, and new directions for its management

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