AML Risk in Epirubicin-Treated Breast Cancer Patients
Abstract & Commentary
William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor for Clinical Oncology Alert.
Synopsis: In an analysis of surveillance data on epirubicin-treated early breast cancer patients, a definite association with late development of acute myelogenous leukemia and myelodysplasia became apparent. The risk, however, was not evident in patients treated with conventional, moderate-dose regimens. Most patients had also received radiation therapy and cyclophosphamide and, for those who received high cumulative doses of both drugs, the 8-year cumulative probability of developing acute myelogenous leukemia or myelodysplasia approached 5%.
Source: Praga C, et al. Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol. 2005;23:4179-4191.
Over the past decade or so, adjuvant treatment for early breast cancer has intensified and there is currently a large and growing cohort of women who are at risk for treatment-related long-term consequences. In the current report, Praga and associates reviewed the follow-up of early breast cancer patients treated in 19 randomized trials that included epirubicin to determine incidence, risk, and risk factors for subsequent acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS).
There were a total of 9796 patients included in this analysis (53,080 patient-years). Of the 7110 patients treated with epirubicin-containing regimens (the great majority of whom had also received cyclophosphamide) the 8-year cumulative probability of AML/MDS was 0.55% (95% CI, 0.33%-0.78%). The risk of developing AML/MDS increased in relation to planned epirubicin dose per cycle, planned epirubicin dose intensity and administered cumulative doses of epirubicin and cyclophosphamide. Patients with administered cumulative doses of both epirubicin and cyclophosphamide not exceeding those used in standard regimens (< 720 mg/m2 and < 6300 mg/m2, respectively) had an 8-year cumulative probability of developing AML/MDS of 0.37% (95% CI, 0.13%-0.61%) compared with 4.97% (95% CI, 2.06%-7.87%) for those administered higher cumulative doses of both epirubicin and cyclophosphamide.
COMMENTARY
Higher and more frequent dosing of adjuvant chemotherapy is the current trend for treatment of early breast cancer and the long-term consequences of such an approach need to be comprehensively evaluated. The leukemogenic effect of alkylating and radiation are well described, but less is known about leukemia that occurs in recipients of other drugs. Epirubicin is a DNA topoisomerase II-targeted inhibitor about which there have been isolated reports of secondary leukemia.1,2 As a result, the manufacturer (Pharmacia & Upjohn, now Pfizer) extended its routine monitoring to include an extensive analysis to determine the risk of such an occurrence. The monitoring plan included all patients entered into 19 randomized, adjuvant chemotherapy clinical trials that included epirubicin in at least one arm. This extensive and well-constructed analysis allows the following conclusion. The cumulative probability of epirubicin-associated AML/MDS may be correlated with the cumulative doses of both epirubicin and cyclophosphamide. The risk is low (comparable to that observed with hormonal therapy) when the cumulative doses of epirubicin and cyclophosphamide are low, but the risk rises sharply with increasing cumulative doses. Nonetheless, the therapeutic benefit from adjuvant therapy with both of these agents is well established; and even at the higher doses, the increased risk is likely outweighed by the efficacy of treatment. Nonetheless, the data presented would question the advisability of higher or more intensively scheduled regimens.
Although the epirubicin dose relationship with leukemia development was clearly demonstrated, most patients also received radiation and/or cyclophosphamide. Although thought to induce leukemia by different mechanisms, the component of risk due to epirubicin could not be clearly segregated from that of these other factors. Furthermore, inasmuch as cumulative dose has proven to be critical, one wonders whether patients previously treated with other drugs in this class (eg, doxorubicin) will be at increased risk.
References
1. Pedersen-Bjergaard J, et al. Acute monocytic or myelomonocytic leukemia with balanced chromosome translocations to band 11q23 after therapy with 4-epi-doxorubicin and cisplatin or cyclophosphamide for breast cancer. J Clin Oncol. 1992;10:1444-1451.
2. Riggi M, Riva A. Therapy-related leukemia: what is the role of 4-epi-doxorubicin? J Clin Oncol. 1993;11: 1430-1431.
In an analysis of surveillance data on epirubicin-treated early breast cancer patients, a definite association with late development of acute myelogenous leukemia and myelodysplasia became apparent. The risk, however, was not evident in patients treated with conventional, moderate-dose regimens. Most patients had also received radiation therapy and cyclophosphamide and, for those who received high cumulative doses of both drugs, the 8-year cumulative probability of developing acute myelogenous leukemia or myelodysplasia approached 5%.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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