Correspondence
Uterine Sarcoma Associated with Tamoxifen Use
N Engl J Med 2002; 346:1832-1833June 6, 2002
- Article
To the Editor:
Between 1978, when tamoxifen was first marketed in the United States, and April 2001, there were 43 cases, reported either to the Food and Drug Administration (FDA) or in the medical literature,1 of uterine sarcoma that developed in women in the United States who had been receiving tamoxifen (Nolvadex, AstraZeneca) for breast cancer; these included one woman with ductal carcinoma in situ and one with stage I breast cancer. In addition, uterine sarcoma was reported to have developed in 116 women in other countries after they had taken tamoxifen for breast cancer. Primary histologic findings were consistent with a diagnosis of malignant mixed mullerian tumor. The affected women in the United States had a median age of 63 years; those in other countries had a median age of 65 years. The median duration of exposure to tamoxifen was five years in both groups. Documentation of risk factors, stage at presentation, and follow-up was incomplete, but 27 of 86 women whose cancer had been classified according to the staging system of the International Federation of Gynecology and Obstetrics (31 percent) presented with stage III or IV disease, and 38 of the 159 in the two groups combined (24 percent) were reported to have died of progressive endometrial disease.
According to the prescription data for the reporting period,1 the rate of reported cases of uterine sarcoma in women in the United States for whom tamoxifen was prescribed was 0.5 case per 100,000 person-years, as compared with an expected incidence of about 1 to 2 cases per 100,000 person-years.2 However, there is underreporting; when reporting is complete (as it is with the clinical-trial data), the reporting rate exceeds the expected rate.
The data suggest that exposure to tamoxifen is associated with uterine sarcoma, an endometrial cancer with a poor prognosis. The results are consistent with those of a recently reported study3 in which women with long-term use of tamoxifen for breast cancer (those who had been receiving tamoxifen for two or more years) were more likely than nonusers with breast cancer to have endometrial sarcomas. The FDA and the manufacturer of tamoxifen have also discussed the significantly increased incidence of uterine sarcoma (0.17 case per 1000 woman-years) observed in the long-term follow-up of women enrolled in clinical trials of tamoxifen4 and are working together to alert patients and physicians to these new findings.
The advanced stage at diagnosis and the reported deaths from metastatic uterine sarcoma contrast with reports of uterine adenocarcinoma associated with tamoxifen that usually presents at a curable stage (stage I). Surveillance for uterine cancer is indicated for women who are being treated with tamoxifen, especially if they are long-term users. Women should be instructed to report abnormal vaginal bleeding and abdominal pain and pressure to their physicians immediately. A black-box warning about uterine sarcoma, uterine adenocarcinoma, pulmonary embolism, and stroke will be added to the tamoxifen labeling. The warning is most relevant for women who are at high risk for breast cancer and those with ductal carcinoma in situ who take tamoxifen to reduce the risk of invasive breast cancer and for whom a survival benefit of the drug has not been demonstrated.
4 ReferencesDiane K. Wysowski, Ph.D.
Susan Flamm Honig, M.D.
Julie Beitz, M.D.
Food and Drug Administration, Rockville, MD 208571
National Prescription Audit and National Prescription Audit Plus. Plymouth Meeting, Pa.: IMS HEALTH, 1978-2001 (data base).
2
Zimmerman R, Westhoff CL. Gynecologic cancers. In: Neugut AI, Meadows AT, Robinson E, eds. Multiple primary cancers. Philadelphia: Lippincott Williams & Wilkins, 1999:397-416.
3
Bergman L ,Beelen ML ,Gallee MPW , et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000;356:881-887
CrossRef | Web of Science | Medline4
Wickerham DL ,Fisher B ,Wolmark N , et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002;20:2758-2760
Web of Science | Medline
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