**1. Introduction**

148 Cancer of the Uterine Endometrium – Advances and Controversies

Thigpen, J. T., M. F. Brady, R. D. Alvarez, M. D. Adelson, H. D. Homesley, A. Manetta, J. T.

Thigpen, J. T., M. F. Brady, H. D. Homesley, J. Malfetano, B. DuBeshter, R. A. Burger and S.

Thomas, M., A. Mariani, J. D. Wright, E. O. Madarek, M. A. Powell, D. G. Mutch, K. C.

Trimble, E. L., C. Kosary and R. C. Park (1998). "Lymph node sampling and survival in

Uccella, S., K. C. Podratz, G. D. Aletti and A. Mariani (2009). "Lymphadenectomy in endometrial cancer." *Lancet* 373(9670): 1170; author reply 1170-1171. Uccella, S., K. C. Podratz, G. D. Aletti and A. Mariani (2009). "Re: Systematic pelvic

Vergote, I., K. Kjorstad, V. Abeler and P. Kolstad (1989). "A randomized trial of adjuvant

Walker, J. L., M. R. Piedmonte, N. M. Spirtos, S. M. Eisenkop, J. B. Schlaerth, R. S. Mannel, G.

progestagen in early endometrial cancer." *Cancer* 64(5): 1011-1016.

Oncology Group Study LAP2." *J Clin Oncol* 27(32): 5331-5336.

Gynecologic Oncology Group." *J Clin Oncol* 17(6): 1736-1744.

endometrial cancer." *Gynecol Oncol* 71(3): 340-343.

3902-3908.

98-104.

*Oncol* 108(2): 293-297.

Soper and F. T. Given (1999). "Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the

Liao (2004). "Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a gynecologic oncology group study." *J Clin Oncol* 22(19):

Podratz and S. C. Dowdy (2008). "Surgical management and adjuvant therapy for patients with uterine clear cell carcinoma: a multi-institutional review." *Gynecol* 

lymphadenectomy vs no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial." *J Natl Cancer Inst* 101(12): 897-898; author reply 898-899. Urbanski, K., K. Karolewski, Z. Kojs, M. Klimek and T. Dyba (1993). "Adjuvant progestagen

therapy improves survival in patients with endometrial cancer after hysterectomy. Results of one-institutional prospective clinical trial." *Eur J Gynaecol Oncol* 14 Suppl:

Spiegel, R. Barakat, M. L. Pearl and S. K. Sharma (2009). "Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic

Selective Estrogen Receptor Modulators (SERMs) are synthetic compounds originally designed as oral contraceptives in the 1960s. During the ensuing decades, they have been shown to be effective for the prevention of both invasive and *in situ* breast cancer, for the treatment and prevention of osteoporosis, and for the primary prevention of breast cancer. This chapter will review the most important agents focusing on their uterine effect derived from dozens of clinical trials that have explored their efficacy for the listed indications. We will compare and contrast the agents and highlight recent development of newer, more efficacious SERMs that have an improved safety profile.

#### **2. Tamoxifen**

The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. Women at increased risk for breast cancer were randomly assigned to receive placebo or 20 mg/day tamoxifen for 5 years (Fisher et al. 1998). Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the risk of occurrence of breast cancer over time.

Tamoxifen reduced the risk of invasive breast cancer by 49%, with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50–59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed.
