title: Risk of leukemia after chemotherapy and radiation treatment for breast cancer.
abstract: 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.
authors.affiliation: Radiation Epidemiology Branch, National Cancer Institute, Bethesda, Md. 20892.
authors.forename: R E
authors.initials: RE
authors.lastname: Curtis
authors.forename: J D
authors.initials: JD
authors.lastname: Boice
authors.forename: M
authors.initials: M
authors.lastname: Stovall
authors.forename: L
authors.initials: L
authors.lastname: Bernstein
authors.forename: R S
authors.initials: RS
authors.lastname: Greenberg
authors.forename: J T
authors.initials: JT
authors.lastname: Flannery
authors.forename: A G
authors.initials: AG
authors.lastname: Schwartz
authors.forename: P
authors.initials: P
authors.lastname: Weyer
authors.forename: W C
authors.initials: WC
authors.lastname: Moloney
authors.forename: R N
authors.initials: RN
authors.lastname: Hoover
mesh_terms: D000368:Aged; D000477:Alkylating Agents / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D016022:Case-Control Studies; D003131:Combined Modality Therapy / Q000009:adverse effects; D003520:Cyclophosphamide / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007938:Leukemia / Q000209:etiology*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology; D007953:Leukemia, Radiation-Induced / Q000209:etiology; D008558:Melphalan / Q000009:adverse effects; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000209:etiology; D011878:Radiotherapy / Q000009:adverse effects; D011879:Radiotherapy Dosage; D012306:Risk
chemical_list: D000477:Alkylating Agents; D003520:Cyclophosphamide; D008558:Melphalan