Journal of the National Cancer Institute Advance Access originally published online on June 27, 2007
JNCI Journal of the National Cancer Institute 2007 99(13):1051-1052; doi:10.1093/jnci/djm016
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© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Response: Re: Acute Myeloid Leukemia or Myelodysplastic Syndrome Following Use of Granulocyte Colony-Stimulating Factors During Breast Cancer Adjuvant Chemotherapy
Affiliation of authors: Departments of Medicine (DH, AIN), Epidemiology (DH, AIN), and Medicine, Epidemiology, and Health Policy (VG), Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
Correspondence to: Dawn Hershman, MD, MS, Department of Medical Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University, 161 Ft Washington Ave, Rm 1068, New York, NY 10032 (e-mail: dlh23{at}columbia.edu).
We are grateful to the authors of the letters for the opportunity to clarify two issues that were addressed in the Discussion of our paper (1). The first issue, raised by Warren and Brown, addresses the quality and validity of the Surveillance, Epidemiology, and End Results (SEER)–Medicare database. We agree with the authors that our statement implying that Medicare claims had not been validated was misleading. Our intent was to state that each case had not been validated in this particular study, and we thank the authors for clarifying the literature that justifies the methodology we used for the sensitivity analysis. They also clarify the utility of the SEER–Medicare database.
Clavarezza et al. address the issue of confounding by indication. As we mentioned in our Discussion, a major limitation of our study is that we could not measure dose and dose intensity for individual patients. However, as we stated, "Adjusting for type of chemotherapy, duration of chemotherapy, radiation exposure, and stage of disease had a minimal effect on the overall hazard ratio." We also addressed the results of the Cancer and Leukemia Group B (CALGB) 9741 trial mentioned by Clavarezza et al., in which only 11 patients (0.5%) developed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after 3 years of follow-up (2). The risk of MDS/AML was the same in patients treated with dose-dense (every 2 weeks) chemotherapy with granulocyte colony-stimulating factor (G-CSF) as in patients treated with chemotherapy at 3-week intervals. Similarly, in the report by Venturini et al. (3), comparing 5-fluorouracil, epirubicin, and cyclophosphamide every 14 days with G-CSF with 5-fluorouracil, epirubicin, and cyclophosphamide every 21 days (control), patients in the control arm who developed bone marrow toxicity had their doses reduced or delayed and did not receive growth factors. Therefore, patients did not receive secondary prophylaxis with G-CSF in either of these trials. None of the patients in either arm of the trial of Venturini et al., consisting of more than 1200 patients followed for a median of 10 years, developed MDS/AML. These very low rates of MDS/AML are substantially lower than have been previously reported in similar clinical trials or in the general population, and the reduction may be related to the lower total dose of anthracycline and/or alkylating agents used in these studies or other selection criteria such as age. Interestingly, the study of Venturini et al., unlike that of the CALGB, did not find a survival benefit of dose-dense therapy administration.
Like all studies of the association between G-CSF and leukemia, our study was limited by our inability to control for confounding by indication. The purpose of G-CSF is to support the marrow in patients treated with more intensive chemotherapy regimens. The more dose intensive the adjuvant therapy regimen, the higher the risk of secondary leukemia.
There is no evidence that prophylactic use of growth factors increases the risk of AML/MDS, because the risk of this complication has not increased over time. We find this reassuring and believe that it supports the use of dose-dense therapy when indicated. The interactive effects of host factors, chemotherapy, and growth factors warrant further investigation, because a recent study now suggests that GM-CSF use may exacerbate the increased AML/MDS risk associated with certain types of chemotherapy in some patients (4). Further research is warranted to clarify the factors that increase the risk of this deadly complication of cancer treatment.
REFERENCES
(1) Hershman D, Neugut AI, Jacobson JS, Wang J, Tsai WY, McBride R, et al. Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst (2007) 99:196–205.
(2) Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol (2003) 21:1431–9.
(3) Venturini M, Del Mastro L, Aitini E, Baldini E, Caroti C, Contu A, et al. Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial. J Natl Cancer Inst (2005) 97:1724–33.
(4) Le Deley MC, Suzan F, Cutuli B, Delaloge S, Shamsaldin A, Linassier C, et al. Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: risk factors for leukemia and myelodysplastic syndrome after breast cancer. J Clin Oncol (2007) 25:292–300.
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Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 1050-1051.
J Natl Cancer Inst 2007 99: 1050.
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