Myelosuppression and Its Consequences in Elderly Patients With Cancer

November 1, 2003

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.

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.

References:

1.

Balducci L: The geriatric cancer patient:Equal benefit from equal treatment. CancerControl 8(2 suppl):1-25, 27-28, 2001.

2.

Edwards BK, Howe HL, Ries LAG, et al:Annual report to the nation on the status ofcancer, 1973-1999, featuring implications ofage and aging on US cancer burden. Cancer94:2766-2792, 2002.

3.

Jemal A, Thomas A, Murran T, et al: Cancerstatistics, 2002. CA Cancer J Clin 52:23-47, 2002.

4.

Yancik R, Ries LA: Aging and cancer inAmerica: Demographic and epidemiologic perspectives.Hematol Oncol Clin North Am 14:17-23, 2000.

5.

Balducci L, Yates J: General guidelinesfor the management of older patients with cancer.Oncology 14:221-227, 2000.

6.

Lyman GH, Balducci L, Agboola Y: Useof colony-stimulating factors in the elderly cancerpatient. Oncology Spectrums 2:414-421,2001.

7.

Balducci L, Hardy CL, Lyman GH: Hemopoieticreserve in the older cancer patient:Clinical and economic considerations. CancerControl 7:539-547, 2000.

8.

Crivellari D, Bonetti M, Castiglione-Gertsch M, et al: Burdens and benefits of adjuvantcyclophosphamide, methotrexate, andfluorouracil and tamoxifen for elderly patientswith breast cancer: The International BreastCancer Study Group trial VII. J Clin Oncol18:1412-1422, 2000.

9.

Dees EC, O’Reilly S, Goodman SN, etal: A prospective pharmacologic evaluation ofage-related toxicity of adjuvant chemotherapyin women with breast cancer. Cancer Invest18:521-529, 2000.

10.

Langer CJ, Manola J, Bernardo P, et al:Cisplatin-based therapy for elderly patientswith advanced non-small-cell lung cancer:Implications of Eastern Cooperative OncologyGroup 5592, a randomized trial. J Natl CancerInst 94:173-181, 2002.

11.

Lyman GH, Morrison VA, Dale DC, etal: Risk of febrile neutropenia among patientswith intermediate-grade non-Hodgkin’s lymphomareceiving CHOP chemotherapy.Leuk Lymphoma 44:2069-2076, 2003. See alsohttp://www.tandf.co.uk/journals.

12.

Caggiano V, Stolshek B, Delgado D, etal: First and all cycle febrile neutropenia hospitalizations(FNH) and costs in intermediategrade non-Hodgkin’s lymphoma (IGL) patientson standard-dose CHOP therapy (abstract1810). Blood 98:431a, 2001.

13.

Christman K, Muss HB, Case DL, et al:Chemotherapy of metastatic breast cancer inthe elderly. The Piedmont Oncology Associationexperience. JAMA 268:57-62, 1992.

14.

Kuderer NM, Cosler L, Crawford J, etal: Mortality and economic impact of hospitalizationwith febrile neutropenia in patientswith breast cancer (abstract 106). Proc Am SocClin Oncol 22:27, 2003.

15.

Zelenetz AD, Reider PA, Delgado DJ:Review of patterns of care among communityphysicians in intermediate grade NHL (IGL)reveals significantly greater planned and delivereddose attenuation in older patients (abstract588). Blood 96:137a, 2000.

16.

Agboola O, Crawford J, Dale DC, et al:Most patients treated with adjuvant chemotherapyfor breast cancer receive substantiallyreduced dose intensity (abstract 110). Proc AmSoc Clin Oncol 22:28, 2003.

17.

Yee KW, Pater JL, Pho L, et al: Enrollmentof older patients in cancer treatment trialsin Canada: Why is age a barrier? J ClinOncol 21:1618-1623, 2003.

18.

Hutchins LF, Unger JM, Crowley JJ, etal: Underrepresentation of patients 65 years ofage or older in cancer-treatment trials. N EnglJ Med 341:2061-2067, 1999.

19.

Kemeny M, Muss HB, Kornblith AB, etal: Barriers to participation of older womenwith breast cancer in clinical trials (abstract2371). Proc Am Soc Clin Oncol 19:602a, 2000.

20.

Dixon DO, Neilan B, Jones SE, et al:Effect of age on therapeutic outcome in advanceddiffuse histiocytic lymphoma: TheSouthwest Oncology Group experience. J ClinOncol 4:295-305, 1986.

21.

Bastion Y, Blay JY, Divine M, et al: Elderlypatients with aggressive non-Hodgkin’slymphoma: Disease presentation, response totreatment, and survival-A Groupe d’Etude desLymphomes de l’Adulte study on 453 patientsolder than 69 years. J Clin Oncol 15:2945-2953, 1997.

22.

Björkholm M, Ösby E, Hagberg H, etal: Randomized trial of r-metHu granulocytecolony-stimulating factor (G-CSF) as adjunctto CHOP or CNOP treatment of elderly patientswith aggressive non-Hodgkin’s lymphoma (abstract2655). Blood 94:599a, 1999.

23.

Cress RD, O’Malley CD, LeiserowitzGS, et al: Patterns of chemotherapy use forwomen with ovarian cancer: A populationbasedstudy. J Clin Oncol 21:1530-1535, 2003.

24.

Mahoney T, Kuo YH, Topilow A, et al:Stage III colon cancers: Why adjuvant chemotherapyis not offered to elderly patients. ArchSurg 135:182-185, 2000.

25.

Chen CI, Skingley P, Meyer RM: A comparisonof elderly patients with aggressive histologylymphoma who were entered or not enteredinto a randomized phase II trial. LeukLymphoma 38:327-334, 2000.

26.

Peake M. Elderly lung cancer patientsin UK are undertreated. Presented at the 96thInternational Conference of the American ThoracicSociety, May 5-10, 2000; Toronto,Ontario, Canada.

27.

Goodwin JS, Samet JM, Hunt WC: Determinantsof survival in older cancer patients.J Natl Cancer Inst 88:1031-1038, 1996.

28.

Bonadonna G, Valagussa P, Moliterni A,et al: Adjuvant cyclophosphamide, methotrexate,and fluorouracil in node-positive breastcancer: The results of 20 years of follow-up. NEngl J Med 332:901-906, 1995.

29.

Budman DR, Berry DA, Cirrincione CT,et al: Dose and dose intensity as determinantsof outcome in the adjuvant treatment of breastcancer. The Cancer and Leukemia Group B. JNatl Cancer Inst 90:1205-1211, 1998.

30.

Epelbaum R, Faraggi D, Ben-Arie Y, etal: Survival of diffuse large cell lymphoma. Amultivariate analysis including dose intensityvariables. Cancer 66:1124-1129, 1990.

31.

Kwak LW, Halpern J, Olshen RA, et al:Prognostic significance of actual dose intensityin diffuse large-cell lymphoma: Results ofa tree-structured survival analysis. J Clin Oncol8:963-977, 1990.

32.

Lepage E, Gisselbrecht C, Haioun C, etal: Prognostic significance of received relativedose intensity in non-Hodgkin’s lymphoma patients:Application to LNH-87 protocol. TheGELA (Groupe d’Etude des Lymphomes del’Adulte). Ann Oncol 4:651-656, 1993.

33.

Rowe JM, Andersen JW, Mazza JJ, et al:A randomized placebo-controlled phase III studyof granulocyte-macrophage colony-stimulatingfactor in adult patients (> 55 to 70 years of age)with acute myelogenous leukemia: A study ofthe Eastern Cooperative Oncology Group(E1490). Blood 86:457-462, 1995.

34.

Early Breast Cancer Trialists’ CollaborativeGroup: Polychemotherapy for earlybreast cancer: An overview of the randomisedtrials. Lancet 352:930-942, 1998.

35.

Rosvold E, Langer CJ, McAleer C, etal: Advancing age does not exacerbate toxicityor compromise outcome in non-small celllung cancer patients receiving paclitaxelcarboplatin(abstract 1846). Proc Am Soc ClinOncol 18:478a, 1999.

36.

Sargent D, Goldberg R, MacDonald J,et al: Adjuvant chemotherapy for colon cancer(CC) is beneficial without significantly increasedtoxicity in elderly patients (Pts): Resultsfrom a 3351 Pt meta-analysis (abstract933). Proc Am Soc Clin Oncol 19:241a, 2000.

37.

Chatta GS, Price TH, Stratton JR, et al:Aging and marrow neutrophil reserves. J AmGeriatr Soc 42:77-81, 1994

38.

Shank WA Jr, Balducci L: Recombinanthemopoietic growth factors: Comparable hemopoieticresponse in younger and older subjects.J Am Geriatr Soc 40:151-154, 1992.

39.

Bertini M, Freilone R, Vitolo U, et al: PVEBEC:A new 8-weekly schedule with orwithout rG-CSF for elderly patients with aggressivenon-Hodgkin’s lymphoma (NHL). AnnOncol 5:895-900, 1994.

40.

Zagonel V, Babare R, Merola MC, et al:Cost-benefit of granulocyte colony-stimulatingfactor administration in older patients with non-Hodgkin’s lymphoma treated with combinationchemotherapy. Ann Oncol 5(suppl 2):127-132,1994.

41.

Zinzani PL, Pavone E, Storti S, et al:Randomized trial with or without granulocytecolony-stimulating factor as adjunct to inductionVNCOP-B treatment of elderly high-gradenon-Hodgkin’s lymphoma. Blood 89:3974-3979, 1997.

42.

de Graaf H, Willemse PH, Bong SB, etal: Dose intensity of standard adjuvant CMFwith granulocyte colony-stimulating factor forpremenopausal patients with node-positivebreast cancer. Oncology (Basel) 53:289-294,1996.

43.

Balducci L, Repetto L: Increased risk ofmyelotoxicity in elderly patients with cancer:The case for routine prophylaxis with colonystimulatingfactor beginning in the first cycleof chemotherapy. Cancer. In press.

44.

Heil G, Hoelzer D, Sanz MA, et al: Arandomized, double-blind, placebo-controlled,phase III study of filgrastim in remission inductionand consolidation therapy for adultswith de novo acute myeloid leukemia. The InternationalAcute Myeloid Leukemia StudyGroup. Blood 90:4710-4718, 1997.

45.

Balducci L, Extermann M: Managementof cancer in the older person: A practical approach.Oncologist 5:224-237, 2000.

46.

Webster J, Lyman GH: Use of G-CSF tosustain dose intensity in breast cancer patientsreceiving adjuvant chemotherapy: A pilotstudy. Cancer Control 3:519-523, 1996.

47.

Zinzani PL, Storti S, Zaccaria A, et al:Elderly aggressive-histology non-Hodgkin’slymphoma: First-line VNCOP-B regimen experienceon 350 patients. Blood 94:33-38,1999.

48.

Gregory SA, Case DC Jr, Bosserman L,et al: 14 day CHOP in patients with aggressivenon-Hodgkin’s lymphoma (NHL): Preliminaryresults (abstract 49). Proc Am Soc Clin Oncol19:15a, 2000.

49.

Moore TD, Patel T, Segal ML, et al: Asingle pegfilgrastim dose per cycle supportsdose-dense (q14d) CHOP-R in patients withNHL (abstract 2245). Blood 100:571a, 2002.

50.

Lyman GH: Risk assessment in oncologyclinical practice: From risk factors to riskmodels. Oncology 17(suppl 11):8-13, 2003(this supplement).

51.

Wilson-Royalty M, Lawless G, PalmerC, et al: Predictors for chemotherapy-relatedsevere or febrile neutropenia: A review of theclinical literature. J Oncol Pharm Pract 7:1-7,2001.

52.

Gomez H, Hidalgo M, Casanova L, etal: Risk factors for treatment-related death inelderly patients with aggressive non-Hodgkin’slymphoma: Results of a multivariate analysis.J Clin Oncol 16:2065-2069, 1998.

53.

Lyman GH, Delgado D: Risk and timingof hospitalization for febrile neutropeniaamong patients receiving CHOP-like regimensfor intermediate-grade non-Hodgkin’s lymphoma(abstract 3085). Blood 100:780a, 2002.

54.

Meza L, Baselga J, Holmes FA, et al:Incidence of febrile neutropenia (FN) is directlyrelated to duration of severe neutropenia (DSN)after myelosuppressive chemotherapy (abstract2840). Proc Am Soc Clin Oncol 21:255b, 2002.

55.

Ozer H, Armitage JO, Bennett CL, et al:2000 update of recommendations for the useof hematopoietic colony-stimulating factors:Evidence-based, clinical practice guidelines.American Society of Clinical Oncology GrowthFactors Expert Panel. J Clin Oncol 18:3558-3585, 2000.