Current Therapeutic Modalities for Advanced Stage and Recurrent Disease

Since 1988, the staging of carcinoma of endometrium has been based on surgico-pathological features (97). A highly abbreviated description of the stages is as follows: stage I—tumor that is confined to the uterine corpus; stage II—tumor that involves the uterine corpus with spread to the uterine cervix; stage III—tumor, which has spread to the uterine serosa or adnexa, is identified in pelvic washing cytology, or involves pelvic or para-aortic lymph nodes; stage IV—tumor that has invaded the bowel or bladder mucosa or metastasized to distant sites. Early stage tumors are further divided according to the presence and depth of myometrial invasion and the histological grade. Prognostication and therapy of endometrial adenocarcinoma are directly related to the stage of disease. The primary treatment of endometrial adenocarcinoma consists of hysterectomy and bilateral salpingo-oophorectomy. Pelvic and para-aortic lymph node sampling is indicated for some patients, largely based on the presence of high risk factors in the initial diagnostic endometrial sample. Additional surgery, including omen-tectomy and multiple peritoneal biopsies is often added for women with UPSC, as peritoneal spread is so common. Patients with endometrial adenocarcinoma, found to have adnexal spread, or pelvic or para-aortic lymph node metastasis at surgery, are at high risk for recurrence. They generally benefit from directed radiation therapy with 5-year survival rates of 35-85% based on the site of extrauterine disease (86,98).

Radiotherapy may also be effective when recurrent endometrial adenocarcinoma is later identified in the vagina or pelvis. In several studies, isolated vaginal recurrences treated with radiation therapy were associated with survival rates of about 40% for 5 or 10 years. But the rate dropped to about 20% when there was recurrent disease in the pelvis, and there were very few survivors with nodal recurrences (99-101). However, most women with either recurrent tumor or multifocal, large volume residual disease after surgery requires some form of systemic therapy, such as chemotherapy or hormonal therapy. Although, it must be acknowledged that these therapies are rarely curative and generally associated with disappointingly low response rates usually of short duration.

In single agent trials, cisplatin, carboplatin, doxorubicin, epirubicin, and paclitaxel each displayed some activity, with response rates usually in the range of 20-25%, the time to progression averaging only about 4-6 months, and the median survival averaging about 10 months (102). The combination of cisplatin and doxorubicin resulted in an increase in the response rate to about 50% and median survivals of about 1 year (102), whereas cisplatin and paclitaxel produces a response in 60-80%.

Estrogens and progesterone cause the proliferation and differentiation of glandular epithelium in the normal menstrual cycle, respectively. As most endometrial adeno-carcinomas contain steroid receptors as measured by either biochemical or immuno-histochemical assay, therapy with a steroid that inhibits cell proliferation would appear logical. In 1965, Kistner observed a histological response in endometrial adenocarcinoma in some women who were treated with progestins (103). More recently, Randall et al. have shown a 75-90% regression of complex atypical hyperplasia and well-differentiated adenocarcinoma in women under the age of 40 who were treated with oral progestin therapy. Similar results were reported by Montz et al. for peri-menopausal women with well-differentiated adenocarcinoma using a progesterone-releasing intrauterine contraceptive device (104). Less favorable response rates of 15-35% have been observed for women with measurable recurrent tumors treated with any of the variety of progestational or antiestrogenic compounds (102,105). Progression of disease typically occurs after about 4 months of therapy and overall survival averages less than 12 months, although there are rare durable complete responses. The duration of the response to progestin therapy might be limited by the physiological effect that progesterone has on rapid downregulation of its own receptor. Based on animal model data in which tamoxifen was found to upregulate ER and PR with less stimulation of growth than estradiol, Mortel et al. (106,107) proposed that continuous administration of tamoxifen and alternating week therapy with medroxyprogesterone acetate might help to increase both the rate and duration of response. In a recent study (108), this strategy produced clinical results that were not dramatically different from pure progestin therapy. Although, hormonal therapy for endometrial adenocarcinoma has been used for more than 40 years, surprisingly little is known about the mechanisms by which progestins produce their response in patients. It is even uncertain whether the effect is associated with apoptotic or necrotic cell death or terminal cell differentiation. Selective estrogen receptor modulators including tamoxifen have also been studied as single agent therapy, with results similar to that of progestins (102). Herceptin is currently being studied in women with recurrent tumors that overexpress the Her 2/neu molecule.

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