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Synopsis: Platinum-based chemotherapy increases the risk of secondary leukemia. Nevertheless, the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia.
Source: Travis LB, et al. N Engl J Med 1999;340:351-357.
Platinum-based chemotherapy is the standard postoperative treatment for most patients with epithelial ovarian cancer. Although there is extensive information regarding the risk of leukemia after chemotherapy for ovarian cancer, it principally relates to alkylating-agent chemotherapy. Except for case reports, there has been no large-scale study of the risk of leukemia in association with platinum-based chemotherapy. Travis and colleagues have conducted a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had received a diagnosis of invasive ovarian cancer between 1980 and 1993. Leukemia developed after the administration of platinum-based therapy in 96 women. These women were matched to 272 control patients. The type, cumulative dose, and duration of chemotherapy and the dose of radiation delivered to active bone marrow were compared in the two groups. Among the women who received platinum-based combination chemotherapy for ovarian cancer, the relative risk of leukemia was 4.0. The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5 and 3.3, respectively.
Travis et al found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum. Radiotherapy without chemotherapy did not increase the risk of leukemia. Travis et al conclude that platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. However, they found that the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia.
Platinum-based chemotherapy is the mainstay of postoperative treatment for the majority of patients with epithelial ovarian cancer. In the United States, the standard practice is to advise this therapy for all such patients, except those with low-risk, early-stage disease. For several years, we have known that alkylating agent chemotherapy-standard treatment for ovarian cancer is particularly associated with an increased risk of secondary leukemia. Certain drugs are more likely to lead to secondary acute nonlymphocytic leukemia than are others. For example, prior studies have indicated, for instance, that melphalan is more leukemogenic than cyclophosphamide. We know that, by its mechanism action of producing intrastrand and interstrand cross-links, platinum drugs function much like alkylating agents. Both carboplatin and cisplatin were found to be associated with an increased risk of leukemia. Intuitively, it makes sense that carboplatin was more leukemogenic than cisplatin since its effects are much more pronounced on the bone marrow. And the same trend has held, namely, that cumulative dose and duration appear to influence the degree of risk. It is important to note that Travis et al have placed their results in the proper context—the substantial benefit of platinum-based chemotherapy far outweighs the small excess risk of leukemia. Nevertheless, this report will evoke anxiety among ovarian cancer patients and their families.