Endometrial cancer tamoxifen

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. 

A 41-year-old female is treated for endometrial cancer with tamoxifen. Of the following, how is tamoxifen classified ... 

Tamoxifen is usually well tolerated. Symptoms of estrogen withdrawal (hot flashes and vaginal bleeding) may occur but decrease in frequency and intensity over time. Tamoxifen increases the risks of stroke, pulmonary embolism, deep vein thrombosis, and endometrial cancer, particularly in women age 50 years or older. 

Tamoxifen and raloxifene reduce the rates of invasive breast cancer in women at high risk for developing the disease. Rates of endometrial cancer and deep vein thromboses are higher in patients receiving tamoxifen but overall quality of life is similar between the two agents. 

O Regan RM, Cisneros GM, England GM, MacGregor JI, Muenzner HD, Assikis VJ, et al. (1998) Effects of the antiestrogens tamoxifen, toremifene, and ICI 182,780 on endometrial cancer growth. J Natl Cancer Inst 90 1552-1555... 

Fig. 10.8. Hazard ratio of presenting an endometrial cancer as the consequence of treatment with tamoxifen or raloxifene (MORE study). Reproduced with permission from Cuzick et al. (2003)...

Kleinman D, Karas M, Danilenko M (1996) Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction of IGF binding proteins. Endocrinology 137 1089-1095... 

A randomized placebo-controlled trial found that 39% of the tamoxifen-treated women had an endometrial abnormality, a percentage that was reduced to 10% of women on placebo (p < 0.0001) (Kedar et al. 1994), though no cases of endometrial cancer were diagnosed in this study. The histological abnormalities found in the tamoxifen group were atypical hyperplasia (16%), proliferative endometrium (13%), polyps (8%), or presence of mitosis (2%). The authors concluded that the predicative value of an endometrium thickness... 

In a case-control study (van Leeuwen et al. 1994) in which 98 cases of invasive endometrial carcinoma were diagnosed at least 3 months after diagnosis of primary breast cancer, it was observed that the use of tamoxifen was associated with a RR of 1.3. The risk appeared to have a tendency to increase during treatment, from 0.6 for less than a year to 3.0 for more than 5 years of treatment. It should be noted that the accumulated dose of tamoxifen was significantly associated with risk of endometrial cancer. However, the average daily dose used (20-40 mg/d) did not seem to influence risk. Other authors have also observed that the increase in risk is only detected when a determined accumulated dose is attained (van Leeuwen et al. 1994 De Muylder et al. 1991). 

The observation that women with breast cancer receiving tamoxifen had a reduced incidence of contralateral cancer was the basis for the NSABP-PI study, a randomized, double-blind, placebo-controlled trial that began in 1992. The main objective was to ascertain whether tamoxifen might effectively reduce the risk for breast cancer in women with a high risk of developing this disease. A total of 13,388 women > 35 years old were randomized to either tamoxifen (20 mg/d) or placebo for 5 years. In 1998, the trial was prematurely interrupted as the hypothesis of the study was confirmed (Fisher et al. 1998). However, the reduction in breast cancer risk with tamoxifen was accompanied by an increase in the incidence of invasive endometrial cancer (mean RR = 2.53). The increased risk was seen principally among women > 50 years old with a RR of 4.01, while among women < 49 years old the RR was 1.21. 

According to results from clinical trials, the agonistic effects of tamoxifen detected in animals were also observed in the human uterus as it produces a trophic effect and an increase in the incidence of endometrial pathology, which is related to endometrial thickening (> 4 mm). Its use seems to be associated with an increase in endometrial cancer, which is related to the length of treatment and the accumulated dose of tamoxifen. Nevertheless, these tumors do not seem to be more aggressive or to have a worse prognosis than those found in women who do not follow this treatment or who receive hormone therapy. 

Fisher B (1996) A commentary on endometrial cancer deaths in tamoxifen-treated breast cancer patients. J Clin Oncol 14 1027-1039... 

Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM (1994) Endometrial cancer in tamoxifen-treated breast cancer patients findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14). J Natl Cancer Inst 86 527-537... 

Swerdlow AJ, Jones ME, British Tamoxifen Second Cancer Study Group (2005) Tamoxifen treatment for breast cancer and risk of endometrial cancer a case-control study. J Natl Cancer Inst 97(5) 375-384... 

Tamoxifen is on oestrogen-receptor antagonist. It is used in post-menopousol women with oestrogen-receptor-positive metastatic breast cancer at a dose of 20 mg doily. It con also be used in combination with chemotherapy. Severe side-effects ore infrequent however, it is associated with a small risk of endometrial cancer. Patients should be informed and reassured that the benefits of the treatment at this dose outweigh the risk. 

The administration of tamoxifen necessitates routine gynaecological monitoring since uterine fibroids and endometrial changes may occur with its use. Prior to starting treatment, patients should be informed of the small risk of endometrial cancer associated with tamoxifen therapy. 

The most frequent adverse reactions to tamoxifen include hot flushes, nausea, and vomiting. The incidence of endometrial cancer shows a twofold increase in women on longterm treatment with tamoxifen. 

Tamoxifen is a partial estrogen agonist in breast and thus is used as a treatment and chemopreventative for breast cancer. Tamoxifen is a full agonist in bone and endometrium, and prolonged use of tamoxifen leads to a fourfold to fivefold increase in the incidence of endometrial cancer. See Chapter 56 for a detailed discussion of the use of tamoxifen in breast cancer. 

Prevention of the expected loss of lumbar spine bone density and plasma lipid changes consistent with a reduction in the risk for atherosclerosis have also been reported in tamoxifen-treated patients following spontaneous or surgical menopause. However, this agonist activity also affects the uterus and may increase the risk of endometrial cancer. 

Some helpful evidence comes from related fields. It should be borne in mind, for example, that the question of an increased risk of endometrial hyperplasia and endometrial cancer also arises in patients with estrogen-producing tumors of the ovaries, obesity, and polycystic ovarian syndrome (101) and in patients with breast cancer who are using tamoxifen (102). 

Many centers continue to examine this and other SERMs, for example in countering menopausal bone loss (16), in the hope that they can take the place of tamoxifen and provide a means of avoiding the risks of such complications as endometrial cancer, cataract, and stroke (17-19). 

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). 

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