Tamoxifen thromboembolism

SERMs Tamoxifen Toremifene 20 mg orally daily 60 mg orally daily Hot flashes, vaginal discharge, mild nausea, thromboembolism, endometrial cancer... 

Tamoxifen 20 mg PO twice a day continuously until progressive disease 10% Thrombocytopenia, anemia, thromboembolism, hot flashes, decreased libido, nausea/ vomiting 1. Protective effect on bone and lipids. 2. Increased risk for endometrial cancer. 

Tamoxifen is discussed in Chap. 61, Breast Cancer raloxifene is discussed in Chap. 3, Osteoporosis. Raloxifene decreases bone loss in recently menopausal women without affecting the endometrium and has estrogen-like actions on lipid metabolism. It may exacerbate vasomotor symptoms, and it increases the risk of venous thromboembolism and stroke. 

Raloxifene treatment of osteoporosis was associated with a 76% risk reduction for estrogen-receptor positive breast cancer. An additional study showed that this reduced risk continues for up to 8 years. Among women at high risk for breast cancer, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer and had a lower risk of thromboembolic events. 

Tamoxifen users present also a doubling incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) (118 vs. 62 cases). This increase is similar to that seen with HRT. There are some aspects of this side effect that should be commented on to improve the management of women eligible for tamoxifen treatment and at risk for DVT (Goldhaber 2005). In the subanalysis of the Italian study (Decensi et al. 2005), the venous thromboembolism definition included DVT, PE, and superficial phlebitis. Most of the VTE that the authors reported were, in fact, cases of superficial phlebitis, whereas the admitted definition of venous thromboembolism excludes this entity. Such conceptual differences, together with differences in age and background characteristics between the four studies, can explain the diversity in the incidences observed. 

Decensi A, Maisonneuve P, Rotmenz N et al. (2005) Effect of Tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation 111 650-656... 

Tamoxifen, clomiphene, and raloxifene are orally active. The primary route of excretion of all three drugs is in the feces. The undesirable effects common to all three of these SERMs are increased frequency of hot flashes and increased risk of thromboembolism. Both effects are attributable to their estrogenic activity. 

There have been an increased number of incidences of endometrial changes, thromboembolic events, and uterine malignancies while using tamoxifen. 

Of 8028 postmenopausal women with receptor-positive early breast cancer who were randomly assigned doubleblind to letrozole, tamoxifen, or a sequence of these agents for 5 years, 7963 were included in an analysis of cardiovascular events over a median follow-up time of 30 months (8). There was a similar overall incidence of cardiac adverse events (letrozole 4.8% tamoxifen4.7%), but more grade 3-5 events with letrozole (2.4% versus 1.4%), an excess that was only partly attributable to prior hypercholesterolemia. There were more thromboembolic events with tamoxifen (3.9% versus 1.7% overall and 2.3% versus 0.9% for grade 3-5 events). There were no significant differences between tamoxifen and letrozole in the incidence of hypertension or cerebrovascular events. 

The risk of venous thromboembolism in women taking anastrozole is lower than that in women taking tamoxifen (1.6% versus 2.4%) (9), but still higher than in the untreated population. Cases of pulmonary embolism have been reported in an 80-year-old woman taking anastrozole (10) and a 72-year-old woman taking letrozole (11). 

Reports of adverse reactions to raloxifene should be considered alongside those reported for tamoxifen and other anti-estrogens. However, earlier reports have pointed to a considerable increase in thromboembolism, as has some recent large-scale work (3), and it would be premature to draw final conclusions about the conditions in which it can safely be used. 

The use of tamoxifen to prevent breast cancer has been reviewed (8). The merits of using tamoxifen to prevent mammary carcinoma in women who have never had the disease but are believed to be at high risk have been disputed (9), but it is clear that it would involve very long treatment and that one s view of the adverse effects might need to be revised for this class of users. The available data after 5,10, and 15 years of follow up confirmed an increase in the incidence of endometrial cancer and of thromboembolic complications and suggested ocular toxicity, but these effects were not common and should be more than balanced by the reduced risk of coronary heart disease and osteoporosis (8). 

The risks of venous thromboembolism in women with and without breast cancer have been analysed and are summarized in Table 1 (37). In one case tamoxifen was associated with myocardial infarction (38). 

When tamoxifen 20 mg/day was compared with equieffective doses of anastrozole in 668 patients with advanced breast tumors that were hormone receptorpositive or of unknown receptor status, tamoxifen produced too high a rate of thromboembolism and vaginal bleeding to be considered the treatment of choice (51,52). 

Decensi A, Maisonneuve P, Rotmensz N, Bettega D, Costa A, Sacchini V, Salvioni A, Travaglini R, Oliviero P, D Aiuto G, Gulisano M, Gucciardo G, Del Turco MR, Pizzichetta MA, Conforti S, Bonanni B, Boyle P, Veronesi U. Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation 2005 111 650-6. 

Rutqvist LE, Mattsson AThe Stockholm Breast Cancer Study Group. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. J Natl Cancer Inst 1993 85(17) 1398 106. 

Tamoxifen 20 mg/d orally Transient flare of tumor symptoms Menopausal symptoms, fluid retention and edema, thromboembolic events, increased incidence ofendometrial hyperplasia and cancer... 

Among the adverse effects, climacteric-like complaints predominate, reflecting the decline in estrogen levels. Unlike the SERMs, tamoxifen, which is used for the same indication, aromatase inhibitors do not promote endometrial growth and do not increase the risk of thromboembolic complications. 

Ovarian ablation (oophorectomy) is considered by some to be the endocrine therapy of choice in premenopausal women and produces similar overall response rates as tamoxifen. Medical castration with an LHRH analog, goserelin, leuprolide, or triptorelin, is a reversible alternative to surgery. Progestins are generally reserved for third-line therapy. They cause weight gain, fluid retention, and thromboembolic events. 

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