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Endometrial Cancer: Recent Developments in Evaluation and Treatment

Endometrial Cancer: Recent Developments in Evaluation and Treatment

ABSTRACT: Endometrial carcinoma is the most common gynecologic malignancy in the United States. Most cases are diagnosed at an early stage. However, the outcome for women diagnosed with advanced-stage disease remains poor. The etiology of most endometrial carcinomas stems from the effects of excess estrogen, whether this comes from exogenous or endogenous sources. Differences in epidemiology and presentation suggest the existence of two forms of endometrial cancer: those related to and those unrelated to hormonal stimulation. Most women with endometrial cancer present with abnormal uterine bleeding; endometrial sampling is essential to exclude endometrial carcinoma in such patients. Endometrial cancer is surgically staged, and staging usually includes a hysterectomy and bilateral salpingo-oophorectomy. Lymphadenectomy also should be performed in selective cases to better assess disease spread and to evaluate the need for adjuvant therapy. Adjuvant treatment may include the use of radiation, progestins, or cytotoxic chemotherapeutic agents. Several clinical trials are underway to compare these treatment modalities, as well as to determine the optimal combination of active chemotherapeutic agents, such as doxorubicin, platinum agents, and paclitaxel (Taxol). [ONCOLOGY 13(12):1665-1675, 1999]

Introduction

In the United States, an estimated 37,400 women
will develop uterine cancer in 1999 and an estimated 6,400 women will
die of the disease.[1] The incidence of this cancer varies throughout
the world, with more women in industrialized countries being
afflicted. Carcinoma of the endometrium is the most common
gynecologic malignancy among US women, who have a lifetime risk of
developing the disease of approximately 2%.

Fortunately, the majority of cases of endometrial cancer are
diagnosed at an early stage, when surgery alone may be adequate for
cure. The rate of 5-year survival for women with stage I endometrial
cancer is as high as 95%; however, the 5-year survival rate for women
with stage III or IV disease is only 26%.[2]

Great strides have been made in our understanding of endometrial
cancer over the past decade. The etiologic role of estrogen
therapies, including the use of hormone replacement and tamoxifen
(Nolvadex), has been the focus of several studies. The protective
benefits of oral contraceptive pills and progestin therapies have
been well established. Surgical staging can be tailored to the
individual patient, both by using the laparoscope to minimize
surgical morbidity and by modifying the extent of tissue sampling
based on histopathologic risk. For advanced or recurrent disease,
more active chemotherapeutic agents are available as well, with many
ongoing clinical trials.

Risk Factors

Unopposed Estrogens

Most of the risk factors for endometrial carcinoma are associated
with increased estrogen exposure, either exogenous or endogenous.
Examples of increased exogenous exposure include the use of estrogen
replacement therapy or tamoxifen, while increased endogenous estrogen
exposure may stem from obesity, anovulatory cycles, and
estrogen-secreting tumors (Table 1).[3-5]

Obesity and infertility are significant risk factors for the
development of this cancer. Excessive adipose tissue is a site of
conversion of androstenedione to estrone, as well as aromatization of
androgens to estradiol. Nulliparity, by itself, probably does not
increase the risk of endometrial cancer, but rather, the association
lies with anovulatory cycles and the lack of a progestin effect
during the luteal phase.

With respect to exogenous estrogen exposure, the risk of endometrial
cancer is increased in women using combination hormone therapy, even
when cyclical progestin therapy is added to an estrogen. In a
case-control study, Beresford et al found that women taking unopposed
estrogens had a relative risk of endometrial cancer of 4.0 (95%
confidence interval [CI], 3.1 to 5.1).[6] In women who took more than
5 years of hormone therapy that included a progestin for less than 10
days per month, the relative risk of endometrial cancer was 4.8 (95%
CI, 2.0 to 11.4). Women who used hormone therapy with a progestin for
10 to 21 days per month had a relative risk of 2.7 (95% CI, 1.2 to 6.0).

This study is limited by its retrospective case-control design, which
relies on patient recall. However, it suggests the need for
additional investigation.

The use of oral contraceptives has consistently been shown to
decrease the risk of endometrial and ovarian cancer. The Cancer and
Steroid Hormone (CASH) study demonstrated that women using
combination oral contraceptives for at least 12 months had a 0.6 (95%
CI, 0.3 to 0.9) relative risk of endometrial cancer, as compared with
those who had never used oral contraceptives.[7] The protective
effects of oral contraceptives were found to persist even 15 years
after their use ceased.

Current low-dose oral contraceptives prevent pregnancy primarily
through a progestin effect. Similarly, the benefits of oral
contraceptives in reducing endometrial cancer risk are also likely
related to the effects of progestin in suppressing endometrial proliferation.

Family history also contributes to the risk of endometrial cancer. In
women with the hereditary nonpolyposis colorectal cancer (HNPCC)
syndrome, endometrial cancer is the second most common malignancy,
with an incidence of 20% to 40%.[8] A site-specific endometrial
cancer syndrome also has been suggested from pedigree analysis and
population-based studies.[9]

Tamoxifen

As the most commonly diagnosed cancer among US women, breast cancer
has a far greater impact than endometrial cancer, the most common
gynecologic malignancy. Tamoxifen, a nonsteroidal estrogen with
antiestrogenic activity, is commonly used in the adjuvant treatment
of women with breast cancer and as therapy for recurrent disease.
Tamoxifen also recently received FDA approval for use in reducing the
risk of breast cancer in high-risk women. The divergent activity of
tamoxifen in different tissues is well recognized; it suppresses the
growth of breast tissue (ie, acts as an estrogen antagonist) but
stimulates the endometrial lining (ie, has estrogen-agonistic effects).

Both the National Surgical Adjuvant Breast and Bowel Project (NSABP)
and the Stockholm Breast Cancer Study Group identified an increased
risk for endometrial cancer among breast cancer patients treated with
tamoxifen.[10,11] In one retrospective, case-control study from the
Netherlands, use of tamoxifen for more than 2 years was associated
with a 2.3-fold increased risk of endometrial cancer.[12] Conversely,
another case-control study from Japan, which controlled for the total
dose of tamoxifen exposure, did not find a significant increase in
the incidence of subsequent endometrial cancer.[13] The consensus of
most studies, however, is that there is a two- to threefold increased
risk of endometrial cancer attributable to tamoxifen.[5] Despite
initial reports, more recent studies do not confirm that tamoxifen
use is associated with high-risk histology endometrial cancers.[11,14,15]

In tamoxifen-treated postmenopausal breast cancer patients,
endometrial polyps are a common histopathologic finding. Lahti et al
compared 51 postmenopausal women with breast cancer treated with
tamoxifen (20 to 40 mg/d) for a median duration of 30 months to 52
breast cancer patients who were not treated with tamoxifen.[16]
Endometrial thickening was markedly increased in the
tamoxifen-treated women compared with the controls (mean thickness,
10.4 vs 4.2 mm), and polyps also occurred more frequently in the
tamoxifen recipients (36% vs 10%).

Similarly, Kedar et al performed a randomized, double-blind,
placebo-controlled trial in which 51 of 111 postmenopausal women with
breast cancer were treated with tamoxifen (20 mg/d) for a median
duration of 22 months.[17] Again, greater endometrial thickening and
more endometrial polyps were seen in the women randomized to
tamoxifen. In addition, a proliferative process was noted in the
endometrium of 90% of the tamoxifen-treated patients, as compared
with 39% of the placebo-treated patients.

Endometrial cystic atrophy may also be a common process related to
the estrogenic effect of tamoxifen that is not readily detected by
curettage but is only diagnosed in patients undergoing
hysterectomy.[18] In a cohort of 35 tamoxifen-treated postmenopausal
women, endometrial polyps were found in 66% of patients. Endometrial
cystic atrophy was noted in 9 of 11 patients who underwent
hysterectomy, as compared with only 1 of 24 patients who underwent
hysteroscopy and curettage.

Cystic atrophy may not always develop at the surface of the
endometrium but may be present deeper within the uterine wall and,
thus, still produce endometrial thickening on pelvic ultrasound.
Sonohysterography may be helpful in differentiating between polyps
and endometrial cystic atrophy in women with a thickened endometrium
(see “Presentation and Diagnostic Evaluation” below).

In 1996, the American College of Obstetricians and Gynecologists
(ACOG) issued a committee opinion regarding the role of tamoxifen in
endometrial cancer.[5] The committee concluded that although
tamoxifen is associated with an increased risk of endometrial cancer,
the benefits of treatment outweigh the risks.

Although routine screening for endometrial cancer is not recommended
for patients taking tamoxifen, many patients are being screened.
Certainly, any abnormal bleeding or spotting should be investigated.
Because of the high incidence of cystic atrophy, pelvic ultrasound
may lead to false-positive results. Rather, endometrial biopsy is a
more specific evaluation that may be combined with sonohysterography.

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