Hematopoietic Management in Oncology Practice

This timely and elegant articleby Glaspy reviews current datasupporting the clinical role ofhematopoietic growth factors. As theauthor thoroughly discusses, the introductionof myeloid and erythroidregulatory proteins more than a decadeago has had a dramatic impacton the care of patients with a varietyof cancers and hematologic disorders,as well as other diseases. A large bodyof research allows us to draw someimportant conclusions about the rationaland appropriate use of theseagents. However, as stated in thisarticle, a number of important questionsremain.A variety of preclinical and clinicalfindings demonstrate that granulocytecolony-stimulating factor(G-CSF, filgrastim [Neupogen]) andgranuloctye-macrophage colonystimulatingfactor (GM-CSF, sargramostim[Leukine]) are not identical,nor do they have equivalent biologicactivity. Numerous randomized trialshave demonstrated that in patientsreceiving myelosuppressive chemotherapy,prophylactic use of G-CSFreduces both the degree and durationof neutropenia. Several issues, however,need to be addressed further toallow us to best treat patients, particularlyin the context of cost-effectiveuse of medications and health-careresources.Dose and Schedule
As Glaspy notes, while a doseresponserelationship exists betweenG-CSF and neutrophil production, theoptimal dose and schedule of G-CSFhas not been fully explored. Severalrandomized trials have investigated adose range of G-CSF, with no significantoverall benefit demonstrated thusfar for higher-dose therapy. However,it is reasonable to hypothesize thathigher- dose therapy may be beneficialin selected populations. For example,it is possible that, in patientswho develop febrile neutropenia de-spite receiving conventional doses ofG-CSF, higher-dose therapy may beof benefit. Similarly, limited data havesuggested that, in certain settings, lower-dose therapy may be as effectiveas the current clinically accepted dose.Further exploration of these questionscould have a significant clinicalimpact and allow us to utilize expensiveresources more efficiently. However,as Glaspy notes, it is important toemphasize that the dose and scheduleof G-CSF should not be arbitrarily alteredfrom that which has been proveneffective, until such changes are supportedby appropriate data and studies.Febrile Neutropenia
One clinically important issue reviewedin this article is the treatmentof febrile neutropenia. Specifically,this refers to patients who have notreceived prophylactic G-CSF and developfebrile neutropenia secondaryto myelosuppressive chemotherapy.Management of these patients remainscontroversial. However, several randomizedclinical trials have now addressedthis question. Interestingly, aconsistent finding has been that therapywith G-CSF leads to a statisticallysignificant decrease in the durationof grade 4 neutropenia that is of aclinically meaningful magnitude.Probably what has primarily hinderedclinical acceptance of these data, however,is the lack thus far of a provenbenefit in quality of life, cost-effectiveness,or survival. As to lack of aproven survival benefit, likely this isdue to the fact that the mortality rateassociated with febrile neutropenia inpatients with solid tumors is low, manyof these individual trials were relativelysmall in size, and therefore theyare not adequately powered to detecta mortality difference.Indeed, a recent meta-analysis byClark et al suggests that infectionrelatedmortality may be improved incertain high-risk patients with febrileneutropenia who receive treatmentwith G-CSF.[1] In addition, this metaanalysisconfirms a shorter time toadequate neutrophil recovery with theuse of G-CSF in this setting (previouslydemonstrated in several individualtrials) and a shorter length ofhospitalization.[1] Although it is clearlyimportant to demonstrate this conclusivelywith appropriately designedstudies, one can readily hypothesizethat the use of G-CSF in this settingmay both improve quality of life andreduce overall health-care costs, ifcosts of hospitalization, antibiotics,and so forth are adequately captured.As noted in this review, some ofthese questions have perhaps becomeless critical with the availability of apegylated formulation of G-CSF(Neulasta). This recently approvedcompound has an increased pharmacologichalf-life compared to theparent moiety, and the data have demonstratedthat this new formulation isat least equivalent therapeutically toconventional G-CSF, with no greatertoxicity. However, several of thepoints noted above in regard toG-CSF are equally applicable to pegylatedG-CSF. Although a reasonabledose is known, is this the optimal dosefor all patients? In patients who developfebrile neutropenia despite prophylacticuse of pegylated G-CSF,would a higher dose be of benefit?Would an altered dosing interval beeffective in this setting? Are there specificlow- or moderate-risk patientpopulations in whom lower-dose therapymight be equally effective?Concurrent Use of G-CSFand Chemotherapy
A long-standing theoretical concernin hematopoiesis has been theissue of concurrent use of G-CSF andchemotherapy, which might causemyeloid progenitor cells to be moresensitive to cytotoxic agents asG-CSF induces these cells to enter theproliferative phase of the cell cycle.Thus, concurrent use of G-CSF andchemotherapy might be associatedwith increased severity of neutropenia.Some limited older clinical datahave suggested this possibility.Interestingly, however, at least onerecent clinical trial that addressed thisissue did not demonstrate an adverseeffect for concurrent administration ofG-CSF, compared to conventionallydosed G-CSF administered 24 hoursafter the completion of chemotherapy.This was noted in breast cancer patientswho were receiving high-dosevinorelbine.[2] Additionally, recentpreclinical data suggest that G-CSFcan be safely and effectively administeredconcurrently with at least severalcommonly used cytotoxic agents.This question has assumed greaterimportance over the last couple ofyears with the more frequent use ofweekly and other novel schedules ofcytotoxic agents. In light of the availabilityof pegylated G-CSF, the questionof concurrent use of growth factorassumes even greater importance, becauseif proven effective, it wouldallow a single subcutaneous injectionto be administered immediately afterchemotherapy. The inconvenience ofhaving to wait 24 hours after chemotherapybefore administering growthfactor therapy would be eliminated.Dr. Skip Burris and I are currentlytesting this concept in a randomizedclinical trial evaluating same day vsconventionally dosed pegylatedG-CSF therapy in breast cancer patientsreceiving the TAC regimen(docetaxel [Taxotere], doxorubicin[Adriamycin], cyclophosphamide[Cytoxan, Neosar]).This issue has become particularlytimely in the adjuvant therapy of nodepositivebreast cancer. Cancer andLeukemia Group B 9741 has recentlydemonstrated a significantly superiorefficacy of a dose-dense every-2-weekschedule of doxorubicin, cyclophosphamide,and paclitaxel compared toa conventionally dosed every-3-weekschedule in women with node-positivebreast cancer.[3] This dose-denseregimen was given with conventionalprophylactic G-CSF to all patients.The safety and efficacy of pegylatedG-CSF combined with such dosedensetherapies will also need to beevaluated, given its prolonged clearanceand the possibility of a negativeimpact of concurrent cytotoxics andmyeloid growth factors.Anemia in Cancer Patients
Glaspy nicely reviews some importanthistorical points that put inperspective the current data (and currentpractices) with regard to the treatmentof anemia in cancer patients.Probably to a greater extent than formyeloid growth factors, the optimaldose and schedule of recombinant humanerythropoietin (rhEPO, Epogen,Procrit) and darbepoetin alfa (Aranesp)remain to be defined. The author nicelysummarizes the critical clinical literaturethat defines our current managementof anemia. It is important to notethat recent literature has clearly demonstrateda significant relationship betweenhemoglobin level and quality oflife. Evolving data have shown thatwhat had once generally been consideredmodest decreases in hemoglobinlevels are clearly associated with substantialsymptoms that have a negativeimpact on patients.A thought-provoking point madein this article concerns the evolvingdata supporting the concept that thepatients who may benefit most fromthe treatment of anemia-ie, those withhemoglobin levels of 11 to 12 g/dL-are the ones who have historicallybeen least likely to receive therapy.Indeed, this article nicely puts intoperspective many of the historical issuesand background concepts thathave led to our current approach totreating anemia in cancer patients.Current data supporting the dose andschedule of both rhEPO and darbepoetinalfa are well summarized.The author thoroughly reviews pilotdata suggesting that alternativedoses and schedules of darbepoetinalfa may ultimately be more effectiveand lead to a more rapid rise in hemoglobinlevels. The current widely accepteddosing schedule of darbepoetinalfa (ie, every-2-week therapy) is reviewed,and it is briefly noted thatpilot data suggest that darbepoetin alfamight be effective when administeredon an every-3-week schedule. In fact,a recently published study has demonstratedthat the every-3-week scheduleof darbepoetin alfa is clearlyeffective, and further provides reasonableinsights into the appropriatedose on this schedule.[4]Recent data have demonstrated thateffective treatment of anemia in cancerpatients is associated with significantimprovements in fatigue andother parameters of quality of life.Glaspy notes several interesting pointsthat distinguish the therapy of anemiain renal patients from that in hematologyand oncology patients. Importantly,he explains that the toxicities ofred blood cell growth factors are significantlyless severe in patients whodo not have end-stage renal disease,and that, in fact, we should be exploringapproaches that might lead to morerapid relief of anemia-related symptomsin our patients.Conclusions
Finally, this paper nicely reviewsthe current "hot issues" in the treatmentof anemia, particularly as theyrelate to cancer patients. In additionto further study exploring the doseand schedule of erythropoietin anddarbepoetin alfa, Glaspy points outthat critically undefined relationshipsof iron metabolism, and potentiallyiron therapy, require further research.Provocative recent findings suggest apossible relationship between anemiaand overall survival in a variety ofdifferent cancers. Whether these findingsmerely demonstrate an association,and not a causal relationship,remains to be conclusively proven.Perhaps anemia is a surrogate markerof patients who have poorer survivalfor unrelated reasons. Alternatively,anemia could be causally related tothese outcomes, perhaps due to theimpact of effectiveness of therapies,or perhaps due to other as yet notfully characterized physiologic relationships.Perhaps therapy of anemiamay ultimately lead to better outcomesand cure in patients with a variety ofcancer types.

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.

Clark OA, Lyman G, Castro AA, et al:Colony stimulating factors for chemotherapyinduced febrile neutropenia. Cochrane DatabaseSyst Rev 3:1-30, 2003.

2.

Livingston RB, Ellis GK, Gralow JR, etal: Dose-intensive vinorelbine with concurrentgranulocyte colony-stimulating factor supportin paclitaxel-refractory metastatic breast cancer.J Clin Oncol 15:1395-1400, 1997.

3.

Citron ML, Berry DA, Cirrincione C, etal: Randomized trial of dose-dense versus conventionallyscheduled and sequential versusconcurrent combination chemotherapy as postoperativeadjuvant treatment of node-positiveprimary breast cancer: First report of IntergroupTrial C9741/Cancer and Leukemia Group BTrial 9741 (erratum appears in J Clin Oncol21:2226, 2003). J Clin Oncol 2:1431-1439,2003.

4.

Kotasek D, Steger G, Faught W, et al:Darbepoetin alfa administered every 3 weeksalleviates anaemia in patients with solidtumours receiving chemotherapy; results of adouble-blind, placebo-controlled, randomisedstudy. Eur J Cancer 39:2026-2034, 2003.