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Current Management of Chemotherapy-Induced Neutropenia:The Role of Colony-Stimulating Factors

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ytotoxic chemotherapy suppresses the hematopoi-tic system, impairing host protective mechanisms.ne important consequence, chemotherapy-induced

eutropenia (CIN), places patients at risk of developingever and life-threatening infections. These complica-ions have substantial economic impact and may se-erely affect the quality of life of patients undergoingreatment of cancer. Currently, CIN is managed byelaying and reducing chemotherapy treatment withematopoietic growth factors and with intravenous an-ibiotic therapy. Reducing chemotherapy may compro-ise treatment outcomes in potentially curable malig-

ancies, such as early stage breast cancer and non-odgkin’s lymphoma. Randomized clinical trials have

learly shown that granulocyte colony-stimulating fac-or (filgrastim) and the longer-acting pegylated granu-ocyte colony-stimulating factor pegfilgrastim, whendministered 24 hours after chemotherapy before theccurrence of CIN, are effective in reducing the inci-ence and severity of neutropenia and its complica-ions, including administration of full doses of chemo-herapy without treatment delay. Dose-densehemotherapy, ie, the administration of standard-dosehemotherapy in shorter cycles (made feasible withrowth factor support), has recently been shown tomprove outcomes in early stage breast cancer andon-Hodgkin’s lymphoma. This review summarizes thelinical consequences of CIN and describes currentest practices for the management of patients at risk

or CIN.emin Oncol 30 (suppl 13):3-9. © 2003 Elsevier Inc. Allights reserved.

HE RISK OF death from cancer is a growingworldwide concern. In the United States

lone, approximately 556,500 cancer-relatedeaths are expected in 2003.1 Chemotherapy re-ains the mainstay of cancer treatment, improv-

ng outcomes and survival in many different tumorypes. The dose-response dynamics and toxicitiesf cancer chemotherapy are well known. Myelo-uppression (ie, neutropenia, thrombocytopenia,nd/or anemia as a consequence of suppression ofell formation in the bone marrow) is its majorose-limiting toxicity. Oncologists routinely bal-nce the predicted benefit of full-dose chemother-py versus these toxicities, although nausea, vom-ting, diarrhea, and mucositis are also commondverse effects that threaten patients’ health anduality of life (QOL). Chemotherapy-induced

eutropenia (CIN) is usually a life-threatening

eminars in Oncology, Vol 30, No 4, Suppl 13 (August), 2003: pp 3-9

omplication because it rapidly leads to enhancedusceptibility to infections.

Chemotherapy-induced neutropenia is defineds a reduction in the number of circulating neu-rophils (absolute neutrophil count [ANC])aused by the administration of myelotoxic che-otherapy. Neutropenia is commonly graded on a

cale of 0 to 4 using the common toxicity criteriaf the National Cancer Institute, and grade 4eutropenia is defined by an ANC � 0.5 �09cells/L (Table 1).2

Neutrophils provide the body’s first line of de-ense against bacterial and fungal infections, andccumulation of these cells is responsible for theedness, swelling, and pain that commonly occurt tissue sites of infection. Neutropenic patientsre slow to mount an inflammatory response andherefore may not show the classic signs and symp-oms of infection when tissue invasion occurs.ecause febrile neutropenia ([FN]; fever, defineds a temperature � 38.5°C, with severe neutrope-ia) is associated with potentially severe infection,ncologists have learned to manage this compli-ation as a potentially life-threatening emergency.tandard of care requires that patients with FN bereated with broad-spectrum antibiotics as soon asossible without waiting for the results of bloodultures or other studies.3

Over three decades ago, Bodey et al4 establisheddirect correlation between the depth and dura-

ion of neutropenia and the risk of infection. Theyhowed that the lower the ANC and the longerhe duration of neutropenia, the greater the riskor infection. The risk of developing FN is alsoelated to the duration of CIN; the incidence ofN increases with each consecutive day of severe

From the Department of Medicine, University of Washington,eattle, WA.Dr Dale has received grant or research support from and serves on

he speakers bureau of Amgen.Address reprint requests to David Dale, MD, Department ofedicine, University of Washington, 1959 NE Pacific St, Box

56422, Seattle, WA 98195.© 2003 Elsevier Inc. All rights reserved.0093-7754/03/3004-1302$30.00/0

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doi:10.1016/S0093-7754(03)00326-9

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neutropenia, and chemotherapy patients who havebeen neutropenic (ANC � 0.5 � 109 cells/L) for5 days have a 50% chance of developing FN.5

While it has been difficult to predict whichpatients will develop CIN, and subsequently FN,there are known risk factors that can be classifiedas disease-, patient-, and regimen-specific (Table2). Disease-related risk factors include the type ofcancer and stage of disease.6 For example, patientswith hematologic malignancies are at higher riskfor developing CIN compared with patients withsolid tumors because of the underlying disease andthe intensity of the treatment required. Leukemiapatients on average spend twice as much time inthe hospital for febrile neutropenic complicationsthan patients with solid tumors, and as a grouphave twice as many FN-related deaths.

Patient-specific risk factors include age, perfor-mance status, and concomitant disease. The im-pact of age on susceptibility to CIN has beenfrequently identified as a significant risk factor,although physiologic age (defined by a Compre-

hensive Geriatric Assessment) may be a more ac-curate predictor of risk than chronologic age.7High-risk patients may also have compromisedbone marrow reserves as a result of heavy priortreatment with chemotherapy or previous irradia-tion to marrow-rich body areas such as the pelvis.8Chemotherapy-induced neutropenia may also beexacerbated by the presence of comorbid condi-tions, a poor performance status, more advancedcancer, pre-existing open wounds, or tissue infec-tions.8

Finally, the severity and duration of CIN andFN are influenced by the toxicity of the chemo-therapeutic agent(s) used and by the dose intensityof the regimen. It is commonly recognized thatcertain chemotherapy regimens are more likely tocause myelosuppression than others; however, therelative rates of neutropenic complications associ-ated with individual regimens has not been com-prehensively defined.9 What is known is that therisk of neutropenia depends on the phase of ther-apy, with the well-supported finding of greatestrisk in the earliest cycles.10-12

CONSEQUENCES OF CHEMOTHERAPY-INDUCED NEUTROPENIA

Chemotherapy-induced neutropenia has sub-stantial clinical, economic, and personal conse-quences (Table 3). Most patients with FN requirehospitalization for evaluation, diagnostic proce-dures, and intravenous antibiotic treatment. A

Table 1. National Cancer Institute Common Toxicity Criteria–Grades of Neutropenia

Grade 1 Grade 2 Grade 3 Grade 4

�1.5 � 109 to �2.0 � 109 cells/L �1.0 � 109 to �1.5 � 109 cells/L �0.5 � 109 to �1.0 � 109 cells/L �0.5 � 109 cells/L

Table 2. Factors Identified as Placing Patients atIncreased Risk for Neutropenic Complications

Disease-related Hematologic malignancyBone marrow involvementLiver dysfunctionTime since first relapse � 2 years�3 Organs involved�15 Months from diagnosis to

start of second-line therapyPatient-related Advanced age

Comorbid conditionsPerformance statusEarly hematologic response to

chemotherapyRegimen-related Chemotherapy agent

History of prior chemotherapy● �2 Prior regimens● Number of previous cycles

Indwelling catheter useRadiotherapy

Table 3. Consequences of Chemotherapy-InducedNeutropenia

● Infection● Hospitalization● Administration of antibiotics● Reduced quality of life● Chemotherapy dose delays/reductions● Reduced treatment effectiveness● Increased healthcare expenditures

4 DAVID DALE

recent analysis reported that the average length ofhospital stay was 10 days. During this period, pa-tients are at risk for the acquisition of nosocomialinfections and other hospital complications.13 Arecent survey of the records of more than 40,000nontransplant adult cancer patients found a 10%mortality rate associated with FN, despite bestempiric care.6 Thus, the clinical consequences ofFN can be severe.

Additional consequences include the high coststo be paid both economically and in terms ofpatient QOL.14 The average daily cost of hospital-ization for patients treated for FN in 1994 to 1995was $1,675 to $1,892.15 Total costs varied with thelength of hospital stay, which is primarily deter-mined by the duration of FN, and the severity ofthe patient’s cancer, comorbidities, and infections.Patients hospitalized for the longest time tend tobe older patients (over 65 years of age) and thoseadmitted with FN in addition to other comorbidconditions (eg, complications related to the ma-lignancy itself, infection, and vascular or otherorgan systems).6,10,15

The total cost of CIN and the treatment ofcancer extends beyond direct medical expenses.These expenses include transportation costs andthose for treatments borne by both the patient andcaregivers, as well as the indirect costs associatedwith loss of income. A preliminary study examin-ing the indirect nonhospital expenditures relatedto FN hospitalization estimated these costs at ap-proximately $5,000 per episode, with most of thisamount from lost wages.16

Oncologists and patients recognize that neutro-penia and FN have negative impacts on patients’QOL, as measured by QOL instruments that in-cluded the Psychosocial Adjustment to IllnessScale, the Hospital Anxiety and Depression Scale,and Functional Assessment of Cancer Treatment-Neutropenia (FACT-N). Recent studies providequantitative data on this problem. Chemotherapypatients reported greater fatigue, distress, and im-pairment of normal functioning during their neu-trophil nadir. Low scores correlated with the se-verity of neutropenia and development of FN, andappeared to linger even after ANC recovery.17-19

Additional factors cited as negatively impactingthe well-being of patients hospitalized for FN in-clude separation from home and family members,the fear of infection, and the multiple proceduresassociated with care in the hospital setting.14

CHEMOTHERAPY-INDUCED NEUTROPENIAMANAGEMENT STRATEGIES

The optimal strategy for the management ofCIN is prevention. Neutropenia can be avoided orameliorated by giving less chemotherapy or bystimulating marrow recovery as soon as possibleafter the chemotherapy, using colony-stimulatingfactor (CSFs).

Chemotherapy Dose Delays and Dose Reductions

The maintenance of chemotherapy dose inten-sity has been shown to improve patient outcomesin some settings.20-24 In particular, studies haveshown that for potentially curable cancers such asearly stage breast cancer and non-Hodgkin’s lym-phoma (NHL), it is important to maintain doseintensity to maximize the benefits of treatment. Inearly stage breast cancer, results of a 20-year fol-low-up showed that a delivered dose � 85% ofstandard was the threshold below which survivalwas compromised.20 Similarly, a long-term pro-spective analysis of overall survival (OS) and dis-ease-free survival in 1,550 patients given adjuvantchemotherapy for breast cancer found that after 9years, patients who received a low-dose doxorubi-cin regimen had lower disease-free survival andOS than did patients who received moderate- tohigh-dose doxorubicin and were otherwise compa-rable treatment arms.21

Similar results are seen in NHL. In a retrospec-tive, multivariate analysis of 115 previously un-treated patients with diffuse large-cell lymphoma,it was found that reduced dose intensity during thefirst 12 weeks of therapy was a stronger predictor oftreatment failure than prognostic factors, such asperformance status and the number of extranodalsites of disease.22 More recently, a survey of prac-tice patterns found a significant association be-tween the occurrence of FN, reduced number ofCHOP (cyclophosphamide/doxorubicin/vincris-tine/prednisone) cycles delivered, and decreased5-year OS in patients with aggressive NHL.25

Chemotherapy dose reductions and treatmentdelays are a common practice, but the extent ofthe practice is not well known. A recent review ofover 135 randomized clinical trials reported thatover half the study protocols prescribed dose re-ductions and/or delays in response to neutropenicevents.26 Unfortunately, the resulting chemother-apy dose intensity delivered was not reported in

CURRENT MANAGEMENT OF CIN 5

many of the trials. A second study designed toevaluate practice patterns in the management ofearly stage breast cancer found that 30% of the1,111 patients surveyed received � 85% of thetarget dose intensity recommended for their par-ticular regimen. Neutropenia was the most com-mon cause of dose reduction and delay in chemo-therapy.27 Similarly, another analysis of 20,000breast cancer patients found that more than onethird received a relative dose intensity of less than85% compared with reference standards of adju-vant chemotherapy.28 In this survey, elderly pa-tients were most likely to receive a reduced dose,with almost half receiving a relative dose intensityof less than 85%. Anticipatory chemotherapy dosereduction in elderly patients appears to be com-mon practice, although otherwise healthy olderpatients receive equal benefit if they are treated asaggressively as younger patients.7

Colony-Stimulating Factors and Chemotherapy-Induced Neutropenia

The prophylactic administration of CSF hasprovided considerable benefits to patients treatedwith myelosuppressive chemotherapy and has sub-stantially altered the management of CIN over thelast decade. Lineage-specific cytokines such asgranulocyte CSF (G-CSF) act on committed neu-trophil precursors in the bone marrow, boostingpatients’ innate defense mechanisms by enhancingneutrophil proliferation, differentiation, and func-tional activity.

Filgrastim (recombinant human G-CSF) is in-dicated to decrease the incidence of infection, asmanifested by FN, in patients with nonmyeloidmalignancies treated with myelosuppressive anti-cancer drugs.29 Clinical trials have documentedthat filgrastim is safe and effective in managingCIN.30,31 In the pivotal phase III trial in patientswith small cell lung cancer, filgrastim significantlyreduced the severity and duration of CIN, short-ened the median duration of severe neutropenia (3v 6 days; P � .001), and accelerated recovery ofthe ANC to its prechemotherapy value.30 Theincidence of first-cycle FN and the overall inci-dence of FN were approximately 50% less withfilgrastim.30,31 Hospitalization rates and the use ofintravenous antibiotics were significantly less withfilgrastim (37% v 58%; P � .02, and 39% v 58%;P � .04, respectively).31 Moreover, patientstreated with filgrastim were also able to tolerate

higher chemotherapy dose intensity than patientswho did not receive growth factor support. Only29% required at least one dose reduction (�15%)across all cycles compared to 61% in the placeboarm.31

Optimal clinical benefits of filgrastim areachieved when filgrastim is initiated 24 hours afterchemotherapy and continued until the ANC hasreached 10 � 109/L after its expected nadir, whichrequires approximately 11 daily injections of fil-grastim.30,31 This was confirmed in another studyin which 70% of patients required 10.8 � 1.9 dailyinjections of filgrastim to show an ANC recovery(defined as a postnadir ANC of 10 � 109/L) in thefirst chemotherapy cycle.32 A retrospective analy-sis of medical records from 12 oncology practiceshas also shown a greater risk of FN with less than7 days of prophylactic filgrastim administration ina chemotherapy cycle, or with the lack of primaryprophylaxis with filgrastim.33

Pegfilgrastim, produced by the covalent bindingof a 20-kd polyethylene glycol moiety to the N-terminal of filgrastim, is a sustained duration CSFthat was recently approved for the reduction inincidence of CIN.34 The rationale for its develop-ment and the results of clinical trials are describedelsewhere in this supplement.35 Because of itspharmacokinetic profile, a single once-per-chemo-therapy-cycle dose of pegfilgrastim has been shownto be comparable with repeated daily doses offilgrastim in phase II and III clinical studies.36-38

Phase III clinical trials have shown that pegfilgras-tim is as effective as daily filgrastim in reducing theduration of severe neutropenia, time to ANC re-covery, and the incidence of FN in women withbreast cancer who are undergoing adjuvant che-motherapy.37,38 The advent of pegfilgrastim prom-ises to considerably simplify the management ofCIN, allowing fewer disruptions to the lives ofpatients with cancer.

Quality-of-Life Benefits

Prophylactic CSF also has the potential to pos-itively influence QOL in patients with cancer,because a correlation between severe CIN andimpaired QOL measures has been reported.17,18

These measures include the distress and discomfortof infection and prolonged hospitalization and lesstangible factors such as fatigue or the inconve-nience and anxiety related to reduced functional-ity. Clinical benefits that may translate into im-

6 DAVID DALE

proved QOL include enhanced efficacy ofantibiotics and the ability to increase chemother-apy dose intensity, thereby improving long-termdisease control and clinical outcome.14

Maintaining Dose Intensity

As previously discussed, the maintenance ofchemotherapy dose intensity has been shown toimprove long-term patient outcome by prolongingtime to disease progression and OS in breast can-cer20,21 and NHL patients.22-24 The use of prophy-lactic CSF facilitates the delivery of standard-reg-imen dose intensity. A randomized trial ofprophylactic filgrastim in NHL patients who re-ceived weekly chemotherapy treatment showedthat filgrastim-treated patients developed signifi-cantly less neutropenia, tolerating a medianplanned dose intensity of 95% compared with 83%dose intensity received by the control group.39

Similarly, in breast cancer patients, � 85% ofplanned dose intensity was delivered to 74% ofpatients given filgrastim compared with 45% ofuntreated control patients.40 Initial results from aprospective study in high-risk patients (first-cycleANC nadir � 0.5 � 109/L) reported that fewerpatients received � 85% of the planned dose ontime when administered filgrastim (4.7%) as com-pared with historical controls who were not ad-ministered filgrastim (20%).41 In fact, a review ofrelevant randomized trials concluded that patientswho received prophylactic growth factors such asfilgrastim are only half as likely to require a che-motherapy dose reduction compared with controlsubjects.42

Dose-dense chemotherapy is an emerging strat-egy that aims to improve survival by administeringchemotherapy in shorter cycles. Dose-dense che-motherapy, generally given every 2 weeks, insteadof every 3 to 4 weeks, is based on the principle thatreducing the time between cycles maximizes cellkill by minimizing the time available for tumorregrowth between cycles. To date, several studieshave evaluated dose-dense chemotherapy admin-istered with filgrastim support with promising re-sults. Preliminary results from a phase III studyhave shown that dose-dense CHOP chemotherapyadministered every 14 days improves OS in elderlypatients with aggressive NHL relative to the stan-dard regimen given every 3 weeks.43 Similar ben-efits were recently reported for patients with earlystage breast cancer.44 The Cancer and Leukemia

Group B presented preliminary results from a largephase III randomized study in breast cancer pa-tients, which show that dose-dense adjuvant che-motherapy (in conjunction with filgrastim prophy-laxis) improves survival while reducingneutropenia when compared with conventionalchemotherapy given without filgrastim support.44

CONCLUSIONS

Chemotherapy-induced neutropenia remains asignificant consequence of cytotoxic therapy, plac-ing patients at risk for negative clinical, economic,and humanistic outcomes. The management ofCIN involves two main strategies: modification ofthe chemotherapy regimen and/or the use ofgrowth factors. While effective in minimizing neu-tropenic complications, chemotherapy dose delaysand reductions can compromise treatment out-comes. Despite clear evidence that the mainte-nance of dose intensity correlates to outcome inearly stage breast cancer and NHL, patients withthese malignancies currently receive reduced che-motherapy doses in clinical practice, based onstudies of current practice patterns.

Prophylactic CSF use effectively reduces therisk of CIN and facilitates the delivery of chemo-therapy on schedule at full doses and makes dose-dense chemotherapy feasible. By ameliorating themyelosuppressive effects of chemotherapy, prophy-lactic growth factors may also improve treatmentoutcomes.

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CURRENT MANAGEMENT OF CIN 7

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CURRENT MANAGEMENT OF CIN 9