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):1050-1051; doi:10.1093/jnci/djm014
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Re: Acute Myeloid Leukemia or Myelodysplastic Syndrome Following Use of Granulocyte Colony-Stimulating Factors During Breast Cancer Adjuvant Chemotherapy
Affiliations of authors: Department of Medical Oncology (MC, LDM, PP), and Clinical Epidemiology (PB), National Cancer Research Institute, Genoa, Italy; Department of Medical Oncology, Negrar Hospital, Verona, Italy (MV)
Correspondence to: Matteo Clavarezza, MD, Department of Medical Oncology, National Cancer Research Institute, L.go Rosanna Benzi, n.10 16132, Genoa, Italy (e-mail: matteo.clavarezza{at}istge.it).
Hershman et al. (1) reported an increased risk (hazard ratio [HR] = 2.14) of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) among women with breast cancer aged 65 years or older included in the Surveillance, Epidemiology, and End Results (SEER)—Medicare database who were treated with adjuvant chemotherapy and received granulocyte colony-stimulating factors (G-CSFs) or granulocyte–macrophage colony-stimulating factors as compared with those who did not. Two randomized studies (2,3), evaluating the efficacy of adjuvant G-CSF–supported dose-dense chemotherapy represent an ideal prospective model to verify the leukemogenic effect of G-CSF. Indeed, all patients in the experimental arms received G-CSF, whereas no patient in the control arms received it. In these studies, no increase in the risk of AML or MDS was observed.
Chance is an unlikely explanation for the observed difference between the study of Hershman et al., in which 16 cases of AML or MDS were diagnosed among 906 breast cancer patients treated with G-CSF, for a cumulative incidence of 1.8% (95% confidence interval [CI] = 0.8 to 2.8) at 4 years and of 2.6% (95% CI = 1.3 to 3.9) at 7 years, and the two randomized trials, in which a total of five cases of AML or MDS were diagnosed in 1592 G-CSF–treated patients (0.3%, 95% CI = 0.1 to 0.7): five of 988 patients in the first study (0.5%, 95% CI = 0.2 to 1.1), at a median follow-up of 3 years, and 0 of 604 patients in the second study (0%, 95% CI = 0 to 0.6), at a median follow-up of more than 10 years.
A possible reason for the discrepancies between the results of the randomized studies and the data reported by Hershman et al. may be the different age of the patient populations and the consequently different baseline risks of AML and MDS. Because the SEER–Medicare database included only women aged 65 years and older, Hershman et al. analyzed only this elderly patient population, whereas the two randomized studies included patients of all ages. In the first study, women aged 60 years or older made up 17.5% of the population and women aged 70 years or older made up 2.5%; in the second study, women aged 65 years or older constituted 8.3% of the population.
Finally, the SEER–Medicare database did not record the dose and dose intensity of chemotherapy and therefore the analyses of Hershman et al. did not include the dose of alkylating agents used by the women. Retrospective evaluation of data from several other randomized trials (4) has shown an increased risk of AML or MDS with increasing dose of cyclophosphamide, as compared with the standard dose (the increase ranged from 2.45 to 6.81 as the dose increased, log-rank P value = .0002). A positive, non–statistically significant association was also seen between total dose of G-CSF and incidence of AML or MDS (HR = 2.34, 95% CI = 0.72 to 7.55). Given these findings, chemotherapy dose must not be excluded in the evaluation of the risk factors for AML or MDS because higher doses of chemotherapy are often associated with the use of G-CSF. In multivariable analyses, such as those performed by Hershman et al., residual confounding may arise when no adjustment for dose is performed. Thus, the association between AML or MDS and G-CSF may not be causal but could reflect the underlying use of higher dose of chemotherapy. The contribution of G-CSF to the risk of AML or MDS following chemotherapy requires further study, but its use to support dose-dense chemotherapy that has been shown to improve breast cancer outcome remains appropriate.
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) Smith RE, Bryant J, DeCillis A, Anderson S. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol (2003) 21:1195–204.
Response to this Correspondence
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 1051-1052.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||