Risk of Leukemia after Chemotherapy and Radiation Treatment for Breast Cancer

Few studies have evaluated the late effects of adjuvant chemotherapy for breast cancer. Moreover, the relation between the risk of leukemia and the amount of drug given and the interaction of chemotherapy with radiotherapy have not been described in detail. We conducted a case–control study in a cohort of 82,700 women given a diagnosis of breast cancer from 1973 to 1985 in five areas of the United States. Detailed information about therapy was obtained for 90 patients with leukemia and 264 matched controls. The dose of radiation to the active marrow was estimated from individual radiotherapy records (mean dose, 7.5 Gy). The risk of acute nonlymphocytic leukemia was significantly increased after regional radiotherapy alone (relative risk, 2.4), alkylating agents alone (relative risk, 10.0), and combined radiation and drug therapy (relative risk, 17.4). Dose-dependent risks were observed after radiotherapy and treatment with melphalan and cyclophosphamide. Melphalan was 10 times more leukemogenic than cyclophosphamide (relative risk, 31.4 vs. 3.1). There was little increase in the risk associated with total cyclophosphamide doses of less than 20,000 mg. Although leukemia occurs in few patients with breast cancer, significantly elevated risks were linked to treatments with regional radiation and alkylating agents. Melphalan is a more potent leukemogen than cyclophosphamide or radiotherapy. Low risks were associated with the levels of cyclophosphamide in common use today. Systemic drug therapy combined with radiotherapy that delivers high doses to the marrow appears to enhance the risk of leukemia. (N Engl J Med 1992;326: 1745–51.), SINCE the mid-1970s adjuvant chemotherapy has been widely used to treat breast cancer with regional lymph-node involvement.¹ More recently, systemic drug therapy has been given to women with localized disease, most of whom survive for many years without a recurrence of cancer.² Patients with breast cancer who are treated with chemotherapy, particularly regimens containing melphalan, are at increased risk of secondary leukemia.^{3 4 5} However, the risk associated with cyclophosphamide, the primary alkylating agent used today to treat breast cancer, has not been well explored. Moreover, there are few studies describing the dose–response relation of these drugs, their interaction with radiotherapy, and…