Tamoxifen use is also associated with an increased incidence of deep venous thrombosis and pulmonary emboli. In several adjuvant studies, the incidence ranged from 1% to 2%.[87,93,107,108,109] Clotting factor changes have been observed in controlled studies of prolonged tamoxifen use at standard doses; antithrombin III, fibrinogen, and platelet counts have been reported to be minimally reduced in patients receiving tamoxifen. The relationship of these changes to thromboembolic phenomena is not clear. Tamoxifen use may also be associated with an increased risk of strokes.[109,111,112] In the NSABP Breast Cancer Prevention Trial (NSABP-P-1), this increase was not statistically significant.
Another potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study. The relationship between tamoxifen and ovarian tumors requires further study. Short-term toxic effects of tamoxifen use may include vasomotor symptoms and gynecologic symptoms (e.g., vaginal discharge or irritation). (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.) Ophthalmologic toxic effects have also been reported in patients receiving tamoxifen; patients who complain of visual problems should be assessed carefully.[116,117,118] Because the teratogenic potential of tamoxifen is unknown, contraception should be discussed with patients who are premenopausal or of childbearing age and are candidates for treatment with this drug.
Tamoxifen therapy may also be associated with certain beneficial estrogenic effects, including decreased total and low-density lipoprotein levels.[119,120] A large controlled Swedish trial has shown a decreased incidence of cardiac disease in postmenopausal women taking tamoxifen. Results were better for women taking tamoxifen for 5 years than for women taking it for 2 years. In another trial, the risk of fatal myocardial infarction was significantly decreased in patients receiving adjuvant tamoxifen for 5 years versus those treated with surgery alone. In the NSABP-B-14 study, the annual death rate due to coronary heart disease was lower in the tamoxifen group than in the placebo group (0.62 per 1,000 vs. 0.94 per 1,000), but this difference was not statistically significant. To date, three large controlled trials have shown a decrease in heart disease.[120,121,122]
Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.[123,124,125] In premenopausal women, decreased bone mineral density is a possibility.
Ovarian ablation, tamoxifen, and chemotherapy
The EBCTCG meta-analysis included almost 8,000 premenopausal women who were randomly assigned to undergo ovarian ablation with surgery or radiation therapy (4,317) or ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists (3,408). Overall, ovarian ablation or suppression reduced the absolute risk of recurrence at 15 years by 4.3% (P < .001) and the risk of death from breast cancer by 3.2% (P = .004). No evidence showed that the relative benefit of suppression differed from that of ablation, but the benefit of either was less in patients who received chemotherapy.[Level of evidence: 1iiA]