Myelosuppression and Its Consequences in Elderly Patients With Cancer

ABSTRACT: Cancer is a disease of the elderly, and its incidence and mortalityincrease with age. The number of persons with cancer is expected todouble between 2000 and 2050, from 1.3 million to 2.6 million, withthe elderly accounting for most of this increase. Studies have shownthat otherwise-healthy older patients treated with chemotherapy of similarintensity obtain benefits comparable to those obtained by youngerpatients. However, chemotherapy-induced neutropenia and its complicationsare more likely in older patients; they are also more often hospitalizedbecause of life-threatening infectious complications. Furthermore,most neutropenic episodes in elderly patients occur in the earlycycles of chemotherapy. To minimize the occurrence of chemotherapyinducedneutropenia, older patients are often treated with less-aggressivechemotherapy and with dose reductions and delays, which maycompromise treatment outcome. The proactive management ofmyelosuppression is therefore essential in elderly patients. Research todetermine the predictors for neutropenia has found that age itself is asignificant risk factor. The benefit of treating elderly patients withcolony-stimulating factors is well established, with their use beginningin the first cycle of chemotherapy being crucial for minimizing neutropeniaand its complications and facilitating the delivery of full-dosechemotherapy. Such prophylaxis should be routinely considered in elderlypatients with cancer treated with myelosuppressive chemotherapy.

It has long been recognized thatcancer is primarily a disease of theelderly. Approximately 60% of allnewly diagnosed malignancies are inpersons aged 65 years or older, as are70% of all deaths due to cancer.[1-3]With few exceptions, those malignancieswith the highest incidences-suchas lung, breast, and colon cancer-mainly affect elderly persons.[4] Aslife expectancy in the United Statesincreases and the population ages, asubstantial increase in the number ofpersons with cancer is expected. Infact, the number of persons with canceris expected to double in the next50 years, from 1.3 million in 2000 to2.6 million in 2050.[2]As in younger patients, chemotherapyis the mainstay of treatmentin patients 65 years of age and older,and the benefits of treatment includeextended survival, maintenance of andimprovement in quality of life, andpalliation of symptoms.[5] The elderlyare more susceptible to certain toxicitiesof chemotherapy, however; in particular,myelosuppression and lifethreateningneutropenia are more commonin elderly patients, emphasizingthe need for prophylactic intervention.[6]Chemotherapy-InducedNeutropenia in the ElderlyThe role of age in patients' susceptibilityto the neutropenic complicationsof chemotherapy has been extensivelyexplored. Clinical and experimentalstudies have suggested an age-relateddecline in the number of hematopoieticstem cells, as well as of the abilityof the bone marrow to react to hematopoieticstress, such as hemorrhage orinfection.[7] These findings may inpart explain the higher rates ofmyelosuppression after chemotherapyin the elderly. Studies of the clinicalimpact of myelosuppression in the elderly have consistently found a higherincidence of severe neutropenia andits complications in older patients.

In a study of adjuvant chemotherapyfor breast cancer with cyclophosphamide(Cytoxan, Neosar),methotrexate, and fluorouracil, therates of grade 3 hematotoxic effectswere significantly higher in older patientsthan in younger patients (9.2%vs 4.5%; P < .001).[8] Another studyin early-stage breast cancer found thatthe incidence and severity of neutropeniawere greater and the absoluteneutrophil count nadir was deeper inpatients older than 65 years.[9] Retrospectiveanalysis of data from a largerandomized phase III trial in non-small-cell lung cancer found a significantlyhigher incidence of leukopeniain men 70 years of age or older.[10] Aretrospective study of practice patternsin non-Hodgkin's lymphoma reportedthat the incidence of febrile neutropeniawas 34% in patients aged 65 yearsor older and 21% in younger patients.[11]Not only are neutropenic complicationsmore frequent in the elderly,they are also often more severe, leadingto higher rates of hospitalization,longer hospital stays, and higher mortality.The study of practice patternsmentioned above found that the rateof hospitalization for febrile neutropeniain patients aged 65 years or olderwas nearly double that in younger patients(28% vs 16%) and the durationof the hospitalization was 30%longer.[11] A study of CHOP (cyclophosphamide,doxorubicin HCl, vincristine[Oncovin], prednisone) chemotherapyfor non-Hodgkin'slymphoma reported that the meanlength of stay in hospitalizations forfebrile neutropenia was 9.8 days inelderly patients and 7.0 days inyounger patients.[12]In a study of chemotherapy formetastatic breast cancer the incidenceof life-threatening febrile neutropeniain elderly patients was twice that inyounger patients, and the only treatment-related septic deaths were in theelderly patients.[13] In fact, Kudereret al, after analyzing data from morethan 41,000 adult patients with cancerhospitalized for febrile neutropenia,found that age 65 years or olderwas associated with more than threetimes higher mortality (6.68% vs2.00%).[14]Because of their greater susceptibilityto myelosuppression, elderlypatients are often given lower dosesof chemotherapy-these dose reductionsare often planned, beginning withthe first chemotherapy cycle. A surveyof practice patterns in 2,911 patientswith non-Hodgkin's lymphomareported that treatment with chemotherapywas more likely to begin witha planned average relative dose intensityof 80% or less in older patientsthan in younger patients (28% vs 12%,P < .001).[15] Another survey of practicepatterns, in more than 20,000 patientstreated with adjuvant chemotherapyfor breast cancer, found thattwo-thirds of patients 65 or older weretreated with a dose intensity of lessthan 85%.[16]Bias against elderly patients mayalso be manifested in other ways(Table 1). For example, despite thehigher incidence of cancer in olderpatients, they are substantiallyunderrepresented in clinical trials ofchemotherapy.[17] Clinical trial protocolsfrequently exclude patientsolder than a specified age, owing inpart to concerns about the potential forgreater toxicity. A review of trials conductedby the Southwest OncologyGroup in various malignancies foundthat only 25% of 16,396 study subjectswere 65 or older, even thoughsuch patients accounted for 63% of thepopulation with cancer when thosestudies were conducted.[18] Physicianbias may also play a role in excludingelderly patients from clinical trials. Acase-matched study in younger andolder women with breast cancer foundthat older women were less likely tobe recruited for and enrolled in clinicaltrials even though they met the eligibilitycriteria.[19]Elderly patients are also more likelyto be treated with less aggressive, andpossibly less effective, regimens thanyounger patients. A number of studieshave investigated alternative, non-doxorubicin-containing regimens inelderly patients with non-Hodgkin'slymphoma, and these regimens areassociated with poorer clinical outcomes.[20-22] A study in patients withaggressive lymphoma found that elderlypatients were less likely to betreated with intent for a cure and wereless likely to survive for 5 years orlonger.[25] A review of treatment practicesin non-small-cell lung cancer inthe United Kingdom found that diagnosisand treatment were consistentlyless aggressive in older patients.[26]Published guidelines recommendthat elderly patients be treated withchemotherapy, but sometimes they arenot. Patients aged 75 years or olderwith ovarian cancer were found to besignificantly less likely than youngerpatients to be treated with chemotherapy(58.2% vs 86.1%, P =.001).[23] Mahoney et al found thatelderly patients with stage III coloncancer were less likely to be treatedwith chemotherapy after surgery thanwere younger patients.[24] Suchundertreatment may be a primarycause of the poorer outcomes in elderlypatients.[27] Indeed, the use ofsubstandard chemotherapy doses andregimens has been shown to contributeto lower overall survival in patientswith chemosensitive tumors in severallarge studies with long followups.[20,21,28-32]Otherwise-healthy elderly patientsobtain benefits comparable to thoseobtained by younger patients whenthey are treated with chemotherapy ofsimilar dose intensity.[1] This hasbeen seen in numerous malignancies,including non-Hodgkin's lymphoma,[20] acute myelogenous leukemia,[33] early-stage breast cancer,[34]non-small-cell lung cancer,[10,35]and colon cancer[36] (Table 2). Fitelderly patients should therefore betreated as aggressively and with thesame curative intent as younger patients.The greater susceptibility tomyelosuppression in older patients,however, means that supportive carewith colony-stimulating factor (CSF)and erythropoietic agents must beconsidered.Pharmacologic studies have shownthat, despite the decline in hematopoieticreserves with older age, CSF administrationis effective in elderly patients.It has been shown to producethe same dose-related increases inpeak neutrophil counts in both youngand elderly healthy volunteers.[37]Colony-stimulating factor has alsobeen shown to increase the neutrophilcounts by the same degree in youngand elderly patients with various malignanciestreated with myelosuppressivechemotherapy.[38]Managing neutropenia in elderlypatients with prophylactic CSF hasbeen assessed in a number of randomizedplacebo-controlled studies.[22,35,36,39-42] In four of thesetrials, in elderly patients with non-Hodgkin's lymphoma,[22,39-41] CSFstarted in the first cycle reduced theincidence of grades 3 and 4 neutropeniaand of neutropenic infection by32% to 82% and 32% to 100%, respectively;P < .01 for both.[43] EarlyCSF use is also associated withshorter hospitalizations for febrileneutropenia in elderly patients withbreast cancer,[13] non-Hodgkin'slymphoma,[40] and acute myelogenousleukemia.[33,44,45] In addition,use of CSF in later cycles in patientstreated with adjuvant chemotherapyfor breast cancer has beenshown to increase the proportion ofpatients in whom the dose intensity ofthe chemotherapy is maintained abovethe 85% threshold.[42,46] The use ofCSF early in the course of chemotherapyand throughout all cyclesmakes it possible to deliver standardfull-dose, as well as dose-dense, chemotherapyin older patients, with outcomescomparable to those in youngerpatients.[47-49]

Risk Models for NeutropeniaColony-stimulating factor use inthe first cycle of chemotherapy is effectivein reducing both the incidenceand the severity of neutropenia, as wellas related complications, but its routineuse in all patients treated with chemotherapyis not considered necessaryor cost-effective. As discussed byLyman in this supplement, efforts areunder way to determine the characteristicsof patients that place them atgreater risk for neutropenia and associatedcomplications.[50] The riskmodels that have been developed sofar have found a number of risk factorsfor chemotherapy-induced neutropeniaand neutropenic complications.Advanced age appears to be a generalrisk factor for chemotherapy-inducedneutropenia and its complications ina number of clinical settings.A review of published risk modelsin which multivariate analysis hadbeen performed analyzed a total of 18models, including three that had beenvalidated in separate populations.[6]Advanced age was reported to be anindependent, significant risk factor ineight of the models and had been validatedin at least two of them. In a separatereview of the literature on risk factorsfor chemotherapy-induced neutropenia,nine studies considered the relationbetween advanced age and therisk of severe neutropenia, eight ofwhich found that older patients wereat greater risk and seven of whichfound that the relation was statisticallysignificant.[51]

Because advanced age has beenestablished as a strong risk factor forneutropenic complications, manystudies that have evaluated neutropenicevents in this patient populationhave focused on the timing of complications,it being an important considerationin scheduling and coordinatingpreventive measures, such asprophylactic CSF. It appears that neutropeniccomplications-includingmortality-commonly occur in theearly cycles of chemotherapy in olderpatients. A retrospective analysis ofdata from 267 consecutive elderly patientswith aggressive non-Hodgkin'slymphoma treated with CHOP foundthat 13% of the patients died of treatment-related causes, with 63% of thedeaths occurring in the first cycle ofchemotherapy.[52] Eighty-three percentof these deaths were attributedto infection, and 66% of them werein patients with severe neutropenia(Figure 1).A randomized trial that assessedchemotherapy-induced toxicities in453 elderly patients with non-Hodgkin's lymphoma reported that,depending on the regimen used, 55%to 72% of the neutropenic events occurredin cycle 1 of the chemotherapy.[21] In another study, in 577patients with non-Hodgkin's lymphomatreated with CHOP, 62% of theinitial episodes of febrile neutropeniain elderly patients occurred in cycle 1(Figure 2).[53] A retrospective analysisof data from two clinical trials inpatients with metastatic breast cancertreated with doxorubicin anddocetaxel (Taxotere) reported that75% of all febrile neutropenic eventsoccurred in cycle 1.[54]In summary, there is strong evidencethat age itself is a general riskfactor for severe neutropenia and thatneutropenic complications are mostlikely in cycles 1 and 2 of chemotherapy.Advanced age may also beassociated with other patient characteristicsthat affect that risk. Thus, amore accurate predictor of neutropeniamay be the patient's physiologic,rather than chronologic, age. Nevertheless,the fact that advanced age isa significant risk factor-and in theabsence of other risk factors to determinewhich elderly patients are atgreatest risk-argues for the use ofCSF started in the first cycle of chemotherapyin elderly patients. Such astrategy appears to be most effectivein minimizing neutropenic complicationsand in facilitating the deliveryof full-dose chemotherapy.The current guidelines of theAmerican Society of Clinical Oncology(ASCO) for the use of CSF recommendits use in the first cycle ofchemotherapy in certain populationsof patients who are at higher risk forneutropenic complications. The "specialcircumstances" in these guidelinesinclude poor performance status,advanced cancer, previous radiationtherapy, extensive previous chemotherapy,history of febrile neutropenia,existing neutropenia, and conditionsthat increase the risks of seriousinfection.[55] Advanced age has consistentlybeen found in several riskmodels to be an independent risk factorfor severe neutropenia. In additon,the risk for neutropenia appears to begreatest in the earliest cycles ofchemotherapy and withholdingCSF in older patients until after anevent has occurred may place themat an unacceptably high risk for seriousinfection and death. And, finally,data on elderly patients with variousmalignancies show that they benefitfrom chemotherapy as much asyounger patients when it is administeredat the standard recommendeddoses; early CSF use helps make thispossible.Elderly patients who are treatedwith moderately aggressive chemotherapyshould therefore be considereda special population in whom primaryprophylaxis with CSF is warranted.Such an approach has beenadvocated by an advisory panel of theNational Comprehensive Cancer Network(NCCN); the rationale is thegreater risk of chemotherapy-inducedneutropenia and its complications inelderly patients and the ability ofG-CSF (granulocyte colony-stimulatingfactor) to reduce this risk (Table3). Specifically, the NCCN guidelinesfor the management of elderly patientswith cancer recommend the routineuse of CSF in patients 70 years of ageor older who are treated with CHOPor a regimen with similar dose intensity,and in patients 60 or older whoare treated with induction or consolidationchemotherapy for acute myelogenousleukemia.[5]ConclusionThe elderly are the single largestproportion of patients with cancer, andthe majority of cancer-related deathsoccur in this population. Elderly patientsobtain comparable benefit fromstandard doses of chemotherapy asyounger patients, but they are moresusceptible to the myelotoxic effectsof chemotherapy-in particular lifethreateningneutropenia-which oftenoccur early. Investigation of clinicalrisk factors has consistently found thatadvanced age is a risk factor for neutropeniccomplications. When prophylacticCSF is administered early in thecourse of therapy and continued in allchemotherapy cycles it reduces theincidence and severity of neutropeniaand associated complications, hencemaking it possible to use standarddoses of chemotherapy. Such useshould be routinely considered in elderlypatients treated with moderatelytoxic chemotherapy regimens.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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