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Although a number of small case reports have linked platinum-based chemotherapy regimens to secondary leukemia, this is the first large-scale, multinational study to quantify the risk. Platinum compounds have served as standard treatment for ovarian cancer for two decades and are also used to treat other cancers, including testicular, bladder, lung, endometrial, and head and neck cancers.
Because platinum drugs are widely used, Lois B. Travis, M.D., Sc.D., of the National Cancer Institute's Division of Cancer Epidemiology and Genetics in Bethesda, Md., and first author of the study, noted that the finding may be important for clinicians in other therapeutic settings. But, she emphasized that the risks needed to be weighed against the substantial benefits of the drugs.
"Before platinum-based treatment, only about 40 percent of patients with advanced ovarian cancer responded to therapy, and the median survival was one year," said Travis, citing recently published statistics. "Now with platinum therapies, the clinical response rate is between 60 percent and 70 percent, with a five-year survival of up to 20 percent to 30 percent. It's clear that the significant improvements in patient survival far outweigh the relatively small excess risk of secondary leukemia."
Travis also believes that the study may have important implications for clinicians who are considering the optimal dose of platinum to treat ovarian cancer. The researchers were able to evaluate the risk of leukemia over a wide range of platinum doses and found a clear relationship between risk and dose; at cumulative doses less than 500 mg, women were almost twice as likely to develop leukemia whereas at doses of 1000 mg or more, the risk was between seven and eight times greater than among patients who did not receive platinum agents.
"If these findings are confirmed in other studies," said Travis, "it is very important that any therapeutic benefit from increasing amounts of platinum be carefully weighed against the corresponding risk of subsequent leukemia."
The risk of leukemia was calculated by following over 28,000 women in North America (Connecticut, Iowa, New Jersey, and Ontario) and Europe (Denmark, Finland, and Sweden) who were diagnosed with ovarian cancer between 1980 and 1993. Leukemia developed in 96 women who were then matched with 272 control patients. Most were diagnosed with acute myeloid leukemia or myelodysplastic syndrome. The average time to develop leukemia was four years. The median survival time after diagnosis of secondary leukemia was only three months; most secondary leukemias are resistant to therapy.
Based on these observations and the drug regimens used in their study, the authors estimated that out of 10,000 ovarian cancer patients treated for six months with 500 mg to 1,000 mg of cisplatin, an excess of 21 leukemias might be expected to occur in the following decade; at doses of 1,000 mg and greater, an excess of 71 leukemias might be expected.
Typical therapy for advanced ovarian cancer during the time frame of the study included a combination of an alkylating agent, usually cyclophosphamide, and a platinum complex, either cisplatin or carboplatin. Another alkylating agent, melphalan, was also used. Today, since the approval of paclitaxel (Taxol®), therapy commonly includes paclitaxel and platinum.
Increased risks of secondary leukemia have been well-documented for several other chemotherapeutic drugs, especially the alkylating agents — mechlorethamine, chlorambucil, melphalan, and busulfan. Because the platinum drugs and alkylating agents have similar mechanisms of action in the cell — cross-linking strand(s) of DNA — the increased risks associated with platinum-based therapy regimens were not surprising.
The researchers in the current study also looked at the risks of leukemia associated with melphalan, an alkylating agent known to be linked to increased risks of leukemia, and corroborated previous findings; intravenous melphalan was six times more leukemogenic than platinum. The authors pointed out that the lower risks of leukemia associated with platinum compared with melphalan should provide reassurance to ovarian cancer patients and clinicians because platinum-based chemotherapy is currently considered optimal therapy for most patients with advanced disease.
Another new finding in the current study was that radiation therapy may enhance the risk of leukemia associated with platinum drugs. The researchers recommended
that additional studies be done to investigate the possibility that the risk of leukemia may be heightened when radiation is combined with platinum to treat patients with other cancers, especially cancers of the testis, bladder, or head and neck.
The authors suggested several other areas for future research: Whether other drug combinations which include platinum might be associated with comparably increased risks of leukemia as shown in their study; whether platinum might be linked with excess risks for solid tumors as in laboratory animals; the possible carcinogenic effects of the new oral formulations of platinum; and the leukemia risks of carboplatin vs. cisplatin.
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