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It's estimated that several hundred thousand US women are currently receiving tamoxifen. Ob/gyns, therefore, must be aware of the recommendations regarding management of the drug's potential adverse effects.
Tamoxifen is the most widely prescribed anticancer drug in the world: several million women have taken or are taking this medication. Multiple prospective, randomized, double-blind studies comparing tamoxifen with placebo in thousands of women with breast cancer have been performed. Numerous studies have documented the benefits of tamoxifen for patients with breast cancer and one study suggestsalthough by no means conclusively provesthe potential for prevention in women at high risk for the disease. Yet, the drug has known adverse effects that must be factored into patient management.
In its analysis of the randomized trials of tamoxifen, the Early Breast Cancer Trialists' Collaborative concluded that the drug is beneficial in preventing recurrence of breast cancer or development of contralateral disease in most women who have had breast cancer. This includes both premenopausal and postmenopausal women with either positive or negative lymph nodes, as long as the tumor is estrogen receptor (ER)-positive. In fact, more than 180,000 new invasive breast cancers are diagnosed in the United States each year, and the majority of such tumors are ER-positive. Given these statistics and the fact that studies suggest an optimal duration of tamoxifen use of 5 years, it would appear that several hundred thousand women are on this drug at a given time.
Recent data suggest that tamoxifen is also of benefit to women with ductal carcinoma in situ (DCIS) and recommendations for the drug's use in this setting add many more patients to the equation. A large study evaluating the role of tamoxifen prophylaxis in women at high risk for breast cancer but without the disease concluded that the treated patients had a significantly lower incidence of both invasive carcinoma and DCIS than did those who were randomized to a placebo. Fisher has suggested that there are about 29 million women in the US who could potentially benefit from prophylactic tamoxifen. In these high-risk women, use of the drug could prevent 700,000 invasive and noninvasive primary breast cancers in the US in 5 years. Given all of these data, then, a large number of patients seen by ob/gyns have the potential to be exposed to tamoxifen.
Multiple studies have documented the benefits of tamoxifen in breast cancer patients, yet the drug is not without adverse effects. These include an apparent increased incidence of thromboembolism, cataracts, endometrial pathology, and clinical hormonal effects. In particular, ob/gyns must be familiar with tamoxifen's impact on the endometrium and hormone levels so that they can educate and manage patients at risk for these problems.
Vasomotor complaints. Although not life-threatening, significant vasomotor symptoms and irregular bleeding are noted in 10% to 15% of patients on tamoxifen. Many of these women elect to stop the medication because of these complaints. Some investigators, however, have suggested that hormone replacement therapy, taken along with tamoxifen, may control life-disturbing vasomotor symptoms. Although this strategy is controversial, preliminary experience suggests that it is not detrimental in regard to breast cancer risk.
Endometrial pathology. Tamoxifen's potential effect on the endometrium may be of greater concern. It has been suggested that tamoxifen does have an impact on the endometrium, and is associated with an increased incidence of benign pathology (mainly hyperplasia and polyps) and of endometrial adenocarcinoma. The first report suggesting a link between tamoxifen and endometrial cancerthree cases in breast cancer patients taking the drugwas published in 1985. Since then, this possible association has been evaluated in many retrospective studies and several prospective, randomized studies of tamoxifen versus controls in breast cancer patients. Because tamoxifen is known to cause uterine bleeding, and adenocarcinoma of the endometrium was not a primary objective of the retrospective studies, detection bias certainly could have influenced the retrospective analyses.
Of the 15 studies reported, 12 showed no relationship between tamoxifen and adenocarcinoma of the uterus. In one, the incidence of the disease was decreased, and in another two, the researchers noted an increased incidence. It was the latter two studies that received considerable publicity in the medical and lay press. Yet, the number of cancers seen in these trials that might be associated with tamoxifen decreases considerably when one factors in the increased incidence of endometrial cancer in breast cancer patients, latency, occult disease, and potential surveillance and ascertainment bias.
In a recent case-control study using the SEER database, over 300 breast cancer patients who took tamoxifen and subsequently developed endometrial cancer were compared to over 600 controls (breast cancer patients on tamoxifen who did not develop endometrial cancer). When controlled for confounding factors, no increased risk of endometrial cancer associated with tamoxifen use was noted. In a Japanese study, breast cancer patients were followed for an average of 9 years after diagnosis and underwent endometrial evaluation prior to either going on tamoxifen or not receiving the drug (this was not a prospective, randomized study). A similar incidence of endometrial cancer was noted in both groups. It would appear that if there is an association between tamoxifen and endometrial cancer, it is extremely small.
For an asymptomatic patient on tamoxifen, the American College of Obstetricians and Gynecologists recommends yearly pelvic exams and Pap smears. Special studies to evaluate the endometrium do not appear to be indicated in these women. Obviously, if a woman on tamoxifen has symptoms, her endometrium should be evaluated, following the same protocol that is used for a postmenopausal patient who is not on tamoxifen.
ACOG Committee Opinion. Tamoxifen and endometrial cancer. No. 169, February 1996.
Burnstein L, Deapen D, Cerhan JR, et al: Tamoxifen therapy for breast cancer and endometrial cancer risks. J Natl Cancer Inst. 1999;91:1654-1662.
Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet. 1998;351:1451-1467.
Fisher B. National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial: a reflective commentary. J Clin Oncol. 1999;5:1632-1639.
MacMahon B. Overview of studies on endometrial cancer and other types of cancers in humans: perspective of an epidemiologist. Semin Oncol. 1997;24(Suppl 1):S1-122-S1-39.
Women's Health Watch is designed to provide Contemporary OB/GYN's readers with easy-to-read and concise news capsules on trends impacting obstetrics and gynecology. We will focus on six major topic areas: maternal mortality, prematurity, perinatal mortality, cancer detection, menopause management, and health legislation. Coverage of these subjects will rotate as warranted by developments in the specialty.
William Creasman. Women's Health Watch: Gynecological implications of tamoxifen use. Contemporary Ob/Gyn 2000;10:99-100.