We evaluated the risk of acute nonlymphocytic leukemia, acute myelodysplastic syndrome, and preleukemia in 3633 patients with gastrointestinal cancer who were treated in nine randomized clinical trials. Among 2067 patients given semustine (methyl-CCNU) as adjuvant therapy, leukemic disorders developed in 14, whereas only one leukemic disorder (acute nonlymphocytic leukemia) occurred among 1566 patients given other therapies (relative risk = 12.4; 95 per cent confidence interval = 1.7 to 250). The six-year cumulative mean risk (+/- S.E.) of acquiring a leukemic disorder after treatment with semustine was 4.0 +/- 2.2 per cent; the incidence rate was 2.3 cases per 1000 persons per year. Risk increased significantly with time after treatment. The risk of leukemic disorders did not differ according to sex, race, age at treatment, or initial tumor type, nor was it enhanced by concomitant radiotherapy or immunotherapy. In addition, no excess of acute nonlymphocytic leukemia was seen in 44,370 patients treated for gastrointestinal cancer in Connecticut during the period 1935 to 1974, before the advent of nitrosourea chemotherapy. This study provides quantitative evidence that nitrosoureas are leukemogenic in human beings and confirms previous observations that adjuvant chemotherapy with alkylating agents may increase the risk of leukemia.
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