ANTIMI M

COGNETTI F

CORTESI, Enrico

FERRETTI G

GIANNARELLI D

LOPEZ M

MAROLLA P

PAPALDO P.

TERZOLI E

English

Archivio della ricerca- Università di Roma La Sapienza

Myeloid Toxicity in Breast CancerPatients Receiving Adjuvant Chemo-therapy: What Is the Appropriate Useof Filgrastim?TO THE EDITOR: Wolff et al1 report that the hyperleukocy-tosis event observed in a 67-year-old white woman treated withpreoperative dose-dense doxorubicin and cyclophosphamidefor four cycles followed by paclitaxel for four cycles, at firstsupported by pegfilgrastim 6 mg subcutaneously (SC) on day 2,“raises concerns about the potential overutilization of pegfil-grastim in some patients.”1 The same authors suggest that afterregistering a high day 1 absolute neutrophil count (ANC) itcould be safer and simpler “to switch from pegfilgrastim sup-port to just a few doses of filgrastim, as five or fewer doses offilgrastim might be enough to support adjuvant chemothera-py.”2 Of course, we agree with the observations reported byWolff et al.1We have previously hypothesized2 that 4 every other dayfilgrastim injections might be sufficient to support the dose-dense combination chemotherapy regimen, citing our favorablefindings of this filgrastim schedule (days 6, 8, 10, 12) in con-junction with a biweekly chemotherapy regimen including cis-platin, epirubicin, folinic acid, and fluorouracil administered topatients with advanced gastric cancer.3 This filgrastim scheduleexerted an acceptable protection from hematological toxicity.In fact, 22% of patients experienced neutropenia grade 3 and4 respectively, and only two patients (3.4%) had grade 3febrile neutropenia.Paclitaxel followed by gemcitabine, a regimen generally notrelated to a high risk of febrile neutropenia, has been reported tobe well tolerated in advanced breast carcinoma, even whengiven as an every 2-week schedule (paclitaxel 150 mg/m2, gem-citabine 2,500 mg/m2).4 Grade 3 neutropenia was registered in12% of patients, grade 4 in 17% of patients, and only one patientpresented two episodes of febrile neutropenia that resolved withstandard therapy and did not require granulocyte colony-stimulating factor (G-CSF) support.4 Probably, neither pacli-taxel at 175 mg/m2 every 2 weeks would require G-CSF support,although we think that the use of two prophylactic filgrastiminjections, on days 8 and 12, could reduce adverse effects, prevent chem-otherapy delay, and contemporarily improve the patient’s quality of life.In our study,2 when we evaluated the role of alternativefilgrastim dosing schedules for early-stage breast cancer patientstreated with relatively high-dose epirubicin and cyclophospha-mide (EC), G-CSF was administered from day 8, 24 to 48 hoursbefore the expected nadir, because the onset of myelosuppres-sion by anthracyclines usually takes place 7 days after adminis-tration, and within 24 hours of starting G-CSF injection,neutrophils are rapidly released from the marrow into the cir-culation.5 The G-CSF schedules were as follows: (1) 480 g/d SCdays 8 to 14; (2) 480 g/d SC days 8, 10, 12, and 14; (3) 300 g/dSC days 8 to 14; (4) 300 g/d SC days 8, 10, 12, and 14; and (5)300 g/d SC days 8 and 12. Filgrastim, regardless of the fivetested schedules, significantly reduced the incidence of neutro-penic fever (P  .0007) and stomatitis (P  .04), the need forantibiotics (P  .003), the number of delayed courses(P  .0001), and the number of cycles requiring dose reductions(P  .002) compared with control. As myelopoietic support toEC, no significant differences were found between the five dif-ferent filgrastim schedules; the short schedule (filgrastim 300g/d on days 8 and 12) produced results similar compared withthe daily or every-other-day schedules in all the safety endpoints evaluated.Using prophylactic filgrastim for a maximum of 7 consec-utive days, we observed that the mean peak of ANC exceededapproximately 5 times the upper limit of normal, which indi-cated that, as prophylaxis, the conventional administration offilgrastim and, as a consequence, the use of pegfilgrastim wouldprobably be not necessary during EC or moderately intensivechemotherapy.2 Furthermore, compared with daily filgrastimadministration, schedule 5 demonstrated less grade 1 to 3 bonepain (53% v 29%, respectively; P  .01) and less grade 1 to 2fever (24% v 8%, respectively; P  .04). In addition, we havefound that anemia tended to progressively worsen during chem-otherapy with increasing G-CSF dosage, and that the hemoglo-bin decrease was minimal with the shortened filgrastimschedule (schedule 5).6 Despite the small number of patients ineach group (about 50) and the low power of the study, ourfindings deserve further investigation in larger randomizedclinical trials, in order to improve efficacy, reduce adverse ef-fects, and reduce cost.Finally, considering the widespread use of CSFs in breastcancer women receiving adjuvant chemotherapy, we agree withBurstein7 that it is crucial to assure a continue surveillance tothese patients to characterize short- and long-term myeloidtoxicity of CSFs.Gianluigi Ferretti, Massimo Lopez, and Edmondo TerzoliDepartment of Medical Oncology, Regina Elena Cancer Institute, Rome, ItalyEnrico CortesiDivision of Medical Oncology, University “La Sapienza”, Rome, ItalyMauro AntimiDivision of Medical Oncology, S. Eugenio Hospital, Rome, ItalyPaolo MarollaDivision of Medical Oncology, S. Andrea Hospital, Rome, ItalyDiana GiannarelliBiostatistics Unit, Regina Elena Cancer Institute, Rome, ItalyFrancesco Cognetti and Paola PapaldoDepartment of Medical Oncology, Regina Elena Cancer Institute, Rome, ItalyREFERENCES1. Wolff AC, Jones RJ, Davidson NE, et al: Myeloid toxicity in breast cancerpatients receiving adjuvant chemotherapy with pegfilgrastim support. J ClinOncol 24:2392-2394, 20062. Papaldo P, Lopez M, Marolla P, et al: Impact of five prophylactic filgrastimschedules on hematologic toxicity in early breast cancer patients treated withepirubicin and cyclophosphamide. J Clin Oncol 23:6908-6918, 2005Correspondence5618 JOURNAL OF CLINICAL ONCOLOGY151.100.175.15Information downloaded from jco.ascopubs.org and provided by at Universita La Sapienza on October 25, 2013 fromCopyright © 2006 American Society of Clinical Oncology. All rights reserved.3. Felici A, Carlini P, Ruggeri EM, et al: Bi-weekly chemotherapy with cisplatin,epirubicin, folinic acid and 5-fluororacil continuous infusion plus G-CSF in ad-vanced gastric cancer: A multicentric phase II study. Cancer Chemother Phar-macol 57:59-64, 20064. Colomer R, Llombart-Cussac A, Lluch A, et al: Biweekly paclitaxel plusgemcitabine in advanced breast cancer: Phase II trial and predictive value ofHER2 extracellular domain. Ann Oncol 15:201-206, 20045. Lord BI, Bronchud MH, Owens S, et al: The kinetics of human granulopoi-esis following treatment with granulocyte colony-stimulating factor in vivo. ProcNatl Acad Sci U S A 86:9499-9503, 19896. Papaldo P, Ferretti G, Di Cosimo S, et al: Does granulocyte colony-stimulating factor worsen anemia in early breast cancer patients treated withepirubicin and cyclophosphamide? J Clin Oncol 24:3048-3055, 20067. Burstein HJ: In reply. J Clin Oncol 24:2394-2395, 2006DOI: 10.1200/JCO.2006.07.6398■ ■ ■Authors’ Disclosures of Potential Conflicts of InterestThe authors indicated no potential conflicts of interest.Additional Correspondence available online (http://www.jco.org)Lenalidomide-Induced Warm Autoimmune Hemolytic AnemiaKamran Darabi, Shailaja Kantamnei, and Peter H. Wiernik .......................................................................................................................................................................e59Liver Toxicity After Treatment With Gefitinib and Anastrozole: Drug-Drug Interactions ThroughCytochrome p450?Paolo Carlini, Paola Papaldo, Alessandra Fabi, Alessandra Felici, Enzo Maria Ruggeri, Michele Milella, Mariangela Ciccarese,Carmen Nuzzo, Francesco Cognetti, and Gianluigi Ferretti .......................................................................................................................................................................e60Elderly Patients Have Become the Leading Drug Consumers: It’s High Time to Properly Evaluate NewDrugs Within the Real Targeted PopulationLazzaro Repetto and Riccardo A. Audisio .................................................................................................................................................................................................................e62Correspondencewww.jco.org 5619

Myeloid toxicity in breast cancer patients receiving adjuvant chemotherapy: what is the appropriate use of filgrastim?

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Myeloid toxicity in breast cancer patients receiving adjuvant chemotherapy: what is the appropriate use of filgrastim?

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