Abstract

PURPOSE: To determine the risk factors for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer.

PATIENTS AND METHODS: We conducted a case-control study among women treated for breast cancer between 1985 and 2001 in French general hospitals, cancer centers, or clinics. We included 182 AML and MDS patients and 534 matched controls. Breast cancer characteristics, type of treatment, and family history of cancer were compared in both groups.

RESULTS: The risk of AML/MDS was increased after topoisomerase-II inhibitor-based chemotherapy (P < 10-16) and was higher for mitoxantrone-based chemotherapy than for anthracycline-based chemotherapy (relative risk [RR] = 15.6; 95% CI, 7.1 to 34.2; and RR = 2.7; 95% CI, 1.7 to 4.5, respectively). After adjustment for other treatment components, the risk of AML/MDS in patients who received radiotherapy was multiplied by 3.9 (95% CI, 1.4 to 10.8) but was not increased by alkylating agents. Patients receiving granulocyte colony-stimulating factor (G-CSF) support had an increased risk of AML/MDS (RR = 6.3; 95% CI, 1.9 to 21), even when controlling for chemotherapy doses. Similar results were obtained when AML and MDS were considered separately.

CONCLUSION: This large case-control study demonstrates that the risk of AML/MDS is much higher with mitoxantrone-based chemotherapy than with anthracyclines-based chemotherapy in a population of women recently treated for breast cancer. The risk of AML/MDS associated with mitoxantrone must be kept in mind when using this drug to treat diseases other than breast cancer (eg, prostate cancer or multiple sclerosis). In addition, our study suggests the need to monitor the long-term effects of G-CSF therapy.

Abstract

Regimens of adjuvant chemotherapy for early-stage breast cancer commonly include alkylating agents and anthracyclines. These agents have been associated with treatment-related acute myelocytic leukemia (AML) or myelodysplastic syndrome (MDS). This article reviews the medical literature concerning the incidence, causes, and natural history of treatment-related AML/MDS, with emphasis on the association of these factors with alkylating agents, topoisomerase inhibitors, growth factors, and radiation treatment. Data from 6 completed adjuvant National Surgical Adjuvant Breast and Bowel Project trials that tested regimens containing doxorubicin and cyclophosphamide were reviewed to characterize the incidence of treatment-related AML/MDS. The regimens differed in cyclophosphamide intensity, cumulative cyclophosphamide dose, and the presence or absence of mandated prophylactic support with growth factor and ciprofloxacin. Rates were compared across regimens, by patient age, and by treatment with or without adjuvant in-breast radiation therapy (RT). The relative risk (RR) for the development of treatment-related AML/MDS was greater for patients undergoing the more-intense regimens than for those undergoing standard AC (doxorubicin/cyclophosphamide) regimens (RR, 6.16; P<0.0001). Risk correlated more closely with dose intensity than with cumulative dose, and the data suggested that granulocyte colony-stimulating factor (G-CSF) dose may also be independently correlated with increased risk. Patients who received in-breast RT experienced more secondary AML/MDS than those who did not (RR, 2.38; P=0.006). Patients treated with AC with intensified doses of cyclophosphamide requiring G-CSF support had increased rates of treatment-related AML/MDS, even though the incidence was slight relative to breast cancer relapse. In-breast RT appeared to be associated with an increased risk of AML/MDS.

Abstract

PURPOSE: To quantify the risk of acute leukemia after adjuvant therapy, especially chemotherapy with topoisomerase II inhibitors.

PATIENTS AND METHODS: We performed a population-based study in a cohort of 3,093 women younger than 85 years who resided in the French administrative area of the Côte d'Or, who were given a first diagnosis of primary breast cancer between 1982 and 1996, and who received a curative treatment. Information about therapy and follow-up events was obtained from records of cancer registries that covered this area.

RESULTS: Until December 1998, 10 cases of acute leukemia, including nonlymphoid acute leukemia and refractory anemia with excess of blasts, occurred in patients before any local or distant recurrence. All cases developed in the first 4 years of follow-up. Compared with the general female population, the incidence rate of leukemia was significantly increased in women who received radiotherapy and chemotherapy (standardized incidence ratio, 28.5; P <.0001). A dose-dependent increase in the risk of leukemia was observed in women treated with mitoxantrone. Cox regression analysis showed that the risk of leukemia was significantly lower in patients treated with anthracyclines than in those treated with mitoxantrone at cumulative doses >/= 13 mg/m(2).

CONCLUSION: The combination of adjuvant radiotherapy and chemotherapy with mitoxantrone induces a high risk of acute leukemia in patients with breast cancer. A leukemogenic effect of chemotherapy with anthracyclines cannot be ruled out with certainty. However, there are some suggestions that these topoisomerase II inhibitors might be less leukemogenic than mitoxantrone and could be preferred in an adjuvant setting.