Risk of Leukemia after Chemotherapy and Radiation Treatment for Breast Cancer

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Thursday, June 25, 1992
Rochelle E. Curtis
John D. Boice, Jr.
Marilyn Stovall
Leslie Bernstein
Raymond S. Greenberg
John T. Flannery
Ann G. Schwartz
Peter J. Weyer
William C. Moloney
Robert N. Hoover
Journal Title: 
New England Journal of Medicine

Background 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.

Methods 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).

Results 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.

Conclusions 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.


Curtis RE, Boice Jr JD, Stovall M, Bernstein L, Greenberg RS, Flannery JT, Schwartz AG, Weyer P, Moloney WC, Hoover RN. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. New England Journal of Medicine. 1992 Jun 25;326(26):1745-51.  DOI: 10.1056/NEJM199206253262605